Innate Immune Response

Immunity to pathogens is divided into innate and adaptive immune responses. The innate immune response is the 1st line of defense against a variety of pathogens, including bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview, viruses, and parasites. In essentially the same form, the innate type of immunity is present in all multicellular organisms. The innate immune response is activated within minutes to hours after exposure to an infection, which curtails microbe invasion at the initial stages. The pathogen has specific components recognized by pattern recognition receptors (PRRs). After identification of a microbial invasion, noncellular components (including the complement system and cytokines) act in concert with cellular elements to achieve cell recruitment, direct microbial killing, or phagocytosis induction. The steps all aim to eliminate the pathogen. Antimicrobial mechanisms in phagocytosis include acidification and respiratory/oxidative burst. The process terminates with destruction of the threat while maintaining immunologic homeostasis. The defense is also important in activating the adaptive immune system.

Last update:

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Immune system

The immune system provides defense (immunity) against invading pathogens ranging from viruses to parasites; components are interconnected by blood and lymphatic circulation.

Two lines of overlapping defense:

  • Innate immunity (nonspecific) 
  • Adaptive immunity (based on specific antigen recognition):
    • Cell-mediated immunity: adaptive response in cells/tissues involving the T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
    • Humoral immunity: adaptive response in fluids (“humoral”) involving B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells and immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins

Innate versus adaptive immunity

Table: Innate versus adaptive immunity
Innate immunity Adaptive immunity
Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics Germline encoded Gene rearrangements involved in lymphocyte development
Immune response Nonspecific Highly specific
Timing of response Immediate (minutes to hours) Develops over a longer period of time
Memory response None Responds quickly upon recognition of antigen with memory response
Recognition of pathogen Pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs)
  • Memory cells (T and B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells)
  • Activated B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells
Components
  • Anatomical barriers (e.g., skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin)
  • Chemical and biological barriers (e.g., gastric acid, vaginal flora)
  • Cells (e.g., granulocytes)
  • Secreted proteins:
    • Enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (e.g., lysozyme)
    • Other PRRs (e.g., antimicrobial peptides (AMPs))
    • Cytokines*
    • Complement* system
  • Cell-mediated immunity: T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
  • Humoral immunity: B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
*Mediators with roles in adaptive immunity

Components of the Innate Immune System

Innate immune response

  • Barriers:
    • 1st line of defense (mechanical, chemical, and biological)
    • Define and line surfaces of the body
    • Secrete substances to remove and reduce pathogens
  • Microbe detection: The 1st step is pathogen recognition:
    • Pattern recognition receptors (PRRs): proteins distinguishing self from foreign material and recognizing components specific to microbes:
      • Pathogen-associated molecular patterns (PAMPs): structures conserved among microbial species
      • Damage-associated molecular patterns (DAMPs) (also known as alarmins): endogenous molecules released from damaged cells
    • According to the location of PRR and PAMP interaction, PRRs can be associated with cells as transmembrane or intracellular receptors:
      • Toll-like receptors (TLRs)
      • Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs)  
      • NOD-like receptors (NLRs)
      • C-type lectin receptors (CLRs) 
    • Secreted and circulating PRRs are involved when the interaction occurs in body fluids (bloodstream and interstitial fluids):
      • Antimicrobial peptides (AMPs)
      • Collectins
      • Lectins
      • Pentraxins
      • Antimicrobial oligosaccharides
  • Several processes trigger a breach in barriers → inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation:
    • Occurs in response to infection or injury
    • Results in the cardinal signs (swelling, redness, heat, and pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Once the pathogen is identified via PRRs, proteins are secreted: 
      • Cytokines (functions include recruitment, cell-to-cell communication, and antiviral, antibacterial, and antifungal actions)
      • Chemokines (cell migration)
      • Complement system (“complements” or assists in eliminating microbes)
      • Some PRRs (e.g., AMPs) are also involved in pathogen elimination.
  • Cellular response: Various cells (e.g., phagocytes) are recruited and participate in the microbial killing.
  • The immune response is terminated when a need no longer exists (homeostasis).

Cells of the innate immune system Innate immune system Innate immunity, the 1st protective layer of defense, is a system that recognizes threatening microbes, distinguishes self-tissues from pathogens, and subsequently eliminates the foreign invaders. The response is nonspecific and uses different layers of protection: barriers such as the skin, pattern recognition receptors (PRRs) as well as circulating proteins, and immune cells that help eliminate the microbe. Cells of the Innate Immune System

  • Many subsets of cells involved in the innate response develop from hematopoietic stem cells (HSCs) in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow (a primary lymphoid organ):
    • HSCs → common myeloid progenitor → gives rise to:
      • Granulocytes: professional phagocytes (neutrophils, monocytes, macrophages), eosinophils, basophils, and mast cells
      • Megakaryocytes → platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets
    • HSCs → common lymphoid progenitor → lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes (generally undergo activation and proliferation in secondary lymphoid organs):
      • B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells and T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells: adaptive immunity
      • Natural killer (NK) cells: mostly innate immune response
      • Natural killer T (NKT) cells: bridge innate and adaptive immunity
  • Individually, the cells have varying functions and targets in the immune response.
  • Crucial roles:
    • Phagocytosis: Microbes or damaged particles are engulfed and digested.
    • Antigen presentation: performed by dendritic cells, macrophages, and B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, which facilitate antigen recognition by adaptive immunity
Stem cells differentiate into 2 pathways

Stem cells differentiate into 2 pathways:
Myeloid pathways produce erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes, platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets, and cells of the innate immune response. Lymphoid pathways produce the cells of adaptive response and natural killer cells.

Image by Lecturio.

Barriers

Mechanical barrier

Epithelial cells line body surfaces and are heavily exposed to antigens.

  • Skin keratinocytes: 
    • Express mannose-binding receptors: mediate the killing of Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis
    • Regular shedding and sweat secretion: limits the adhesion and invasion of microorganisms
  • Respiratory, GI, and genitourinary tracts: 
    • Mucus, a ciliated layer, and sloughing: reduce the adherence of microbes in the respiratory tract
    • GI tract peristalsis and urine flow: limits pathogen attachment

Chemical barrier

  • Skin and stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: produce hydrochloric acid to kill bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
  • Saliva and tears produce lysozyme: breaks up bacterial peptidoglycan in the cell wall
  • The respiratory and GI tracts produce defensins: positively charged peptides creating holes/channels in the walls of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview, and viruses
  • Paneth cells (base of intestinal crypts): secrete AMPs, defensin, and lysozyme
  • Surfactant in the alveoli: binds to the microbe surface and facilitates phagocytosis

Biological barrier

Includes:

  • Microbiome (commensal organisms living in and on the body):
    • Nonpathogenic, coagulase-negative Staphylococci: inhibit the growth of Staphylococcus Staphylococcus Staphylococcus is a medically important genera of Gram-positive, aerobic cocci. These bacteria form clusters resembling grapes on culture plates. Staphylococci are ubiquitous for humans, and many strains compose the normal skin flora. Staphylococcus aureus by secreting antimicrobial peptides
    • Dysbiosis: a change in the microbiome composition of the GI tract (seen with antibiotic use), which can lead to Clostridioides difficile infection
  • IgA and IgG

Cell-associated PRRs

Cell-associated PRRs are expressed in various immune cells and can be intracellular (endolysosomal/cytoplasmic) or transmembrane.

TLRs

  • Detect a range of human pathogens
  • 10 well-defined TLRs in humans
  • TLRs recognize a particular microbial building block (e.g., an amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids sequence of endotoxin or peptidoglycan):
    • Transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription factors are activated.
    • The process leads to the synthesis of proinflammatory cytokines and cell surface molecules, ultimately resulting in a rapid innate immune response.
  • TLR1, TLR2, TLR4, TLR5, and TLR6 recognize microbial cell wall components:
    • TLR4 identifies lipopolysaccharide (LPS) in the outer membrane of gram-negative bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview (involved in septic shock Septic shock Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Septic shock is diagnosed during treatment when vasopressors are necessary to control hypotension. Sepsis and Septic Shock).
    • TLR4 binds to viral envelope proteins.
    • TLR5 recognizes flagellin from flagellated bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview.
    • TLR1, TLR2, and TLR6 recognize lipoproteins.
  • TLR3, TLR7, TLR8, TLR9, and TLR10 are cytoplasmic:
    • Recognize nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids derived from organisms
    • Endogenous nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids → implicated in autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity
  • TLR3, TLR4, TLR7, TLR8, and TLR9:
    • Trigger type-1 interferon (IFN) production (e.g., IFN-α, IFN-β)
    • Antiviral activity

Description of different TLRs

Table: Different TLRs
Toll-like receptor Localization Ligand Origin of the ligand
TLR1 Plasma membrane Triacyl lipoprotein Bacteria
TLR2 Lipoprotein Bacteria, viruses, parasites
TLR3 Endolysosome dsRNA Viruses
TLR4 Plasma membrane LPS Bacteria, viruses
TLR5 Flagellin Bacteria
TLR6 Diacyl lipoprotein Bacteria, viruses
TLR7, TLR8 Endolysosome ssRNA Viruses, bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
TLR9 CpG- DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure Viruses, bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, protozoa
TLR10 Unknown Influenza virus Influenza virus Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza, Listeria Listeria Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria Monocytogenes Infections monocytogenes
dsRNA: double-stranded RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure
LPS: lipopolysaccharide
ssRNA: single-stranded RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure
CpG: cytosine-phosphate-guanine
Pattern recognition receptors

Pattern recognition receptors (PRRs):
Phagocytic cells contain PRRs capable of recognizing various pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) (shown as green structures), which are a group of PRRs, recognize different microbial components, including lipopeptide, flagellin, or peptidoglycan. The PRRs can be found on the plasma membrane or intracellularly.
When a PRR recognizes a PAMP, a signal is sent to the nucleus which activates genes involved in phagocytosis, cellular proliferation, enhanced intracellular killing, and the production and secretion of antiviral interferons Interferons Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons and proinflammatory cytokines.

Image: “Pattern recognition receptors” by Nina Parker et al. License: CC BY 4.0

RLRs

  • Located intracellularly (cytoplasmic sensors): recognize the cytoplasm-invading pathogens
  • RIG-I
  • Recognize viral nucleic acids Nucleic Acids Nucleic acids are polymers of nucleotides, organic molecules composed of a sugar, a phosphate group, and a nitrogenous base. Nucleic acids are responsible for storage, replication, and expression of genetic information. The 2 nucleic acids most commonly seen in eukaryotic cells are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic Acids 
  • Activated RLRs increase the synthesis of IFN-α and IFN-β, which increases the response to virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview infection.

NLRs

  • Located intracellularly (cytoplasmic sensors): recognize the cytoplasm-invading pathogens
  • Nucleotide-binding oligomerization domain (NOD)
  • Recognize the structures of bacterial peptidoglycans and muramyl dipeptides
  • Involved in host defense against viruses, parasites, fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview, and intracellular bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview (e.g., Listeria Listeria Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria Monocytogenes Infections
  • Caspase 1 activation: ↑ proinflammatory cytokines, facilitates pyroptosis or inflammatory cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
  • Act synergistically with TLRs

CLRs

  • Expressed on the cell surface with an associated transmembrane domain
  • Recognize carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates on microorganisms such as bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview and fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview:
    • Bacteria and yeasts have mannan on the surface (polysaccharides not found in humans).
    • Mannan-binding lectin (MBL) (also known as mannose-binding protein): 
      • Found in dendritic cells and macrophages binding mannose in microbes
      • Activates complement
      • Opsonin-enhancing phagocytosis
    • Dectin-1: recognizes β-glucan in the fungal cell wall (e.g., Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis)
  • Also responsible for recognizing endogenous proteins from necrotic host cells

Secreted and Circulating PRR

Secreted and circulating PRRs include many proteins (e.g., AMP, lectins, collectins).

AMPs

  • Secreted PRRs: short, positively charged peptides with natural antimicrobial activity 
  • Exhibit activity against bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview, viruses, and protozoa
  • Found primarily: 
    • Within granules of neutrophils 
    • In secretions from epithelial cells covering skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and mucosal surfaces
  • Major functions:
    • Cationic AMPs are electrostatically attracted to the negatively charged bacterial surface (with phospholipids).
    • Interaction between peptides and the microbial membrane leads to:
      • Disruption and permeabilization of the microbial membrane
      • Bacterial death
    • AMPs disrupt cellular processes:
      • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure/ RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure/protein synthesis 
      • Enzymatic activity
      • Cell-wall synthesis
    • Immunomodulatory activities:
      • Stimulation of chemotaxis 
      • Regulation of excessive proinflammatory response (e.g., TLR activity, cytokine production) to avoid harm to the host
      • Regulation of commensal microorganisms by restricting colonization and providing defense against opportunistic bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview

Types of AMPs

  • Defensins:
    • Short peptides with 3 disulfide bonds (protect from protease activity)
    • α-defensins: 
      • Found in neutrophilic granules and intestinal Paneth cells
      • Able to kill microbes directly or indirectly through entrapment in nets
    • β-defensins: 
      • Extensively found in epithelial surfaces (e.g., respiratory tract, GI tract)
      • Trauma or infection increases the production
  • Cathelicidins:
    • LL-37: C-terminal peptide of cathelicidin antimicrobial peptide (CAMP) from neutrophils and epithelial cells induced by vitamin D
    • Play a role in wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing, angiogenesis, and removal of dead cells
    • Neutralizing activity against LPS
  • Other AMPs:
    • AMPs expressed in the eye: 
      • C-terminal fragments of keratin 
      • Lysozyme 
      • Lactoferrin 
      • Lipocalin 
    • AMPs expressed in the urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract
      • Lipocalin 2: defends against uropathogenic Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli 
      • Uromodulin: a protein binding the pili of bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview, limiting bacterial attachment, and facilitating flushing away by urine
    • Hepcidin:
      • Regulates iron metabolism (dietary iron absorption and distribution)
      • Relevant action against iron-dependent organisms such as malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Malaria, tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, and HIV-1

Antibacterial oligosaccharides

  • Found in human milk: provides newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn protection
  • Biofilms utilized by bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview (for protection) are broken down by oligosaccharides.

Lectins

  • Proteins binding to microbial carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates and triggering the lectin complement pathway
  • Examples:
    • Galectin: disrupts bacterial membrane, inhibits influenza virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview replication, and brings on cell apoptosis
    • MBL: identifies mannose residues and opsonizes; activates the complement pathway

Collectins

  • A family of lectins with collagen-like proteins 
  • Bind to carbohydrate or lipid microbial molecules
  • Functions: 
    • Complement activation
    • Opsonization
    • Microbial lysis
  • Members of the family include:
    • C1q
    • MBL: a collectin and acute-phase reactant produced by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver 
    • Surfactant proteins A and D:
      • Produced by alveolar type II cells 
      • Major component of lung surfactant (keeps alveoli open)

Pentraxins

  • Characterized by the C-terminal pentraxin domain with 5 subunits
  • Function: activates the classical pathway of complement with microbial lysis and opsonization
  • The family of proteins includes:
    • CRP: a classic, acute-phase reactant (secreted with TLR activation or as the effect of proinflammatory cytokines)
    • Serum amyloid P (SAP) component: implicated in amyloid deposition disorders such as amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis and Alzheimer disease Alzheimer disease As the most common cause of dementia, Alzheimer disease affects not only many individuals but also their families. Alzheimer disease is a progressive neurodegenerative disease that causes brain atrophy and presents with a decline in memory, cognition, and social skills. Alzheimer Disease
    • Pentraxin 3 (PTX 3)

Complement

Immune responses follow the recognition of pathogen molecules. The complement system is 1 response activated in the cascading fashion to destroy microbes.

Complement system

  • A major component of both innate and adaptive immunity
  • Consists of nearly 60 plasma and membrane proteins with activation occurring in both immune cells and extracellular space. 
  • C1q: 
    • A circulating, cell-associated PRR
    • Part of C1: the 1st component of the complement system
    • When bound by an antibody (fixed to a microbe, immune complex, or damaged tissue) → the complement cascade is triggered
  • Activated via different pathways

Activation pathways

Complement activation is through distinctive pathways (all start with a different initiating molecule), but all produce C3b (the central molecule of the complement cascade):

  • Classical pathway (activity assessed by the CH50 test):
    • Triggered by antigen-binding antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (primarily IgG and IgM)
    • C1 is C1q in the complex with the 2 proteases: C1r and C1s (C1q + C1r + C1s):
      • The C1q subcomponent attaches to the Fc portion of the antibody.
      • C1r autoactivates and cleaves C1s.
    • C1s cleaves C4 and then C2 → fragments of C4 and C2 (C4b and C2b respectively) → C3 convertase (C4b2b)
    • C3 convertase cleaves C3 and produces C3b (acting as an opsonin) and C3a (acting as an anaphylatoxin).
    • C5 convertases (C4b2b3b) are formed from cleaved components.
    • C5 convertases → cleave C5 → C5a (an anaphylatoxin) and C5b (initiates the membrane attack complex (MAC))
  • Lectin pathway: 
    • Also known as the mannan- and mannose-binding pathway
    • Triggered by lectins (proteins recognizing repetitive patterns of carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates (e.g., mannose, N-acetylglucosamine/GlcNAc))
    • MBL binds to mannose.
    • Leads to cleavage of C4 and C2 by MBL-associated serine proteases (MASPs) (similar to C1s and C1r) → C3 convertase (C4b2b)
    • The cascade proceeds as the classical pathway.
  • Alternative pathway:
    • Antibodies or lectins are not needed to activate.
    • Dependent on the constant presence of C3 at low levels in the circulation (“C3 tickover”)
    • Tickover occurs at a rate of 1% per hour in the blood, with C3 landing on healthy tissue or engaging with pathogens or debris:
      • On healthy tissue, C3 undergoes inactivation.
      • Without a target, C3 is removed from circulation. 
      • C3 becomes activated upon encountering pathogens or cell debris.
    • Activated C3 binds factor B → bound factor B is lysed by factor D → produces Ba (released) and Bb → forms C3 convertase (C3bBb) 
    • C3 convertase (C3bBb) is stabilized by properdin → C3bBbP
    • C3 convertase continues cleaving more C3 to C3b → amplification loop leads to large deposits of C3b on the target
    • C5 convertase is formed (C3bBb3b) and C5 is subsequently cleaved.
  • Effectors produced from activated pathways:  
    • Anaphylatoxins: C3a, C4a, and C5a (C5a also facilitates neutrophil chemotaxis)
    • Opsonin: C3b 
    • MAC: C5b to C5b-9 (cytolysis)
  • Inhibitors regulate complement activation of self cells:
    • Decay-accelerating factor (CD55)
    • C1 inhibitor (C1-INH)
Complement initiation pathways

Complement initiation pathways lead to a common terminal pathway:
Grey boxes identify initiation pathways; complement components are identified along the arrows. The classical pathway is activated by antigen-antibody complexes (Ag-Ab complexes) recognized by C1q in complex with C1r and C1s. Proteases C1r and C1s cleave C4 and C2 to generate the classical pathway C3 convertase C4b2b. The lectin pathway is triggered by the binding of mannose-binding lectin (MBL) or ficolins to carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates on the target membrane.
The MBL-associated serine proteases (MASPs) then cleave C4 and C2 generating the C3 convertase C4b2b. The alternative pathway is triggered when the low levels of C3b protein directly bind a microbe, foreign material, or damaged tissue. When C3b binds with factor B, C3bB is formed. Factor B is cleaved by factor D to form an alternative pathway C3-convertase (C3bBb). The convertase is stabilized by properdin. C3b opsonizes targets for phagocytosis and B-cell activation.
All 3 initiation pathways converge on C3 with distinct C3 convertases cleaving C3 to generate anaphylatoxin C3a and more C3b to form the C5 convertases (C4b2a3b and C3bBb3b). C5 convertase then cleaves C5 into C5a and C5b. The anaphylatoxins C3a, C4a, and C5a can attract/activate inflammatory cells and contract smooth muscle through receptors C3aR and C5aR. The membrane attack complex (MAC) forms when C5b binds C6, C7, C8, and multiple copies of C9. Membrane attack complex pores can cause cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death by osmotic flux.

Image: “Complement initiation pathways” by Girardi G. License: CC BY 4.0

Major functions

Ultimately, the complement pathways aim to eliminate microbes and cellular debris/apoptotic cells:

  • Anaphylatoxins (C3a–C5a) cause:
    • Chemotaxis (leading leukocytes to inflammatory sites)
    • Release of mediators (e.g., histamine from mast cells)
    • Activation of nonimmune cell types (including epithelial and endothelial cells)
    • Contraction of smooth muscles
    • Dilation of blood vessels and exudation of plasma/cells
  • Opsonization through identification of foreign materials and damaged self, which facilitates:
    • The immediate killing of the opsonized target
    • Transfer by erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes to tissue macrophages in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver or spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen
    • Activation of B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells (leading to antigen production and immunologic memory)
  • Cell lysis via the MAC eliminates targets:
    • Disruption of the integrity of cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane (via pore-forming proteins)
    • Bacterial cell lysis

Cytokines

Cytokines are soluble proteins released by different cells, which play overlapping roles in innate and adaptive immunity like the complement system.

Major cytokines

  • Target cell actions:
    • Autocrine (target cell is the same cell secreting the cytokine) 
    • Paracrine (nearby target cell)
    • Endocrine (cytokine is secreted into circulation to act on a distant target)
  • General overview of key functions:
    • Inflammatory cytokines in early response to infection (mediating fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever and sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock): 
      • Tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF))-ɑ
      • Interleukin-1 (IL-1) 
      • Interleukin-6 (IL-6)
    • Chemotaxis: interleukin-8 (IL-8)
    • T-cell proliferation and activation: interleukin-2 (IL-2)
    • Th2 differentiation and proliferation: interleukin-4 (IL-4)
    • B-cell class switching to IgE and IgG: IL-4
    • B-cell class switching to IgA: interleukin-5 (IL-5)
    • Antiinflammatory (attenuates the immune response): interleukin-10 (IL-10), transforming growth factor-β
    • Antiviral ( DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure/ RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview) activity: IFN-ɑ, IFN-β, IFN-ɣ
  • Notable sources:
    • Macrophages secrete: IL-1, IL-6, IL-8, interleukin-12 (IL-12), TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)
    • All T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells secrete: IL-2, interleukin-3 (IL-3)
    • Th1 cells secrete: IFN-ɣ
    • Th2 cells secrete: IL-4, IL-5, IL-10

Description of cytokines

Table: Cytokines
Cytokines Source Function and activity
IL-1 Monocytes, macrophages, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, fibroblasts, most epithelial cells
  • Fever, acute inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock
  • Upregulates adhesion molecules
  • Neutrophil recruitment
  • Osteoclast-activating factor
IL-2 T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
  • T cell activation and proliferation
  • NK cell proliferation and activation
IL-3 T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, NK cells, mast cells Hematopoiesis progenitor stimulation
IL-4 T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, mast cells, basophils
  • Th2 differentiation and proliferation
  • B-cell maturation and class switch to IgE and IgG
IL-5 T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, mast cells, eosinophils
  • Eosinophil growth and differentiation
  • B-cell growth, class switch to IgA
IL-6 Monocytes, macrophages, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, fibroblasts, most epithelial cells
  • Fever, acute phase production
  • T- and B-cell growth
IL-7 Bone marrow, thymic epithelial cells Differentiation of B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, and NK cells
IL-8 Monocytes, macrophages, T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, neutrophils, fibroblasts, endothelial cells, epithelial cells
  • Major neutrophil chemotactic factor
  • Angiogenesis
IL-9 T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
  • Proliferation of mast cells
  • T-cell growth
IL-10 Monocytes, macrophages, T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, keratinocytes, mast cells
  • Antiinflammatory
  • Attenuation of immune response (↓ cytokines, inhibits T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells and NK cells)
IL-11 Bone marrow stromal cells
  • Acute phase production
  • ↑ megakaryocyte formation and maturation
IL-12 Activated macrophages, dendritic cells, neutrophils
  • Formation of Th1 cells
  • ↑ IFN-ɣ
IFN-ɣ T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, NK cells
  • Regulates activation of macrophages and NK cells
  • Activates macrophages → granuloma
TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) Monocytes, macrophages, mast cells, basophils, eosinophils, NK cells, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, fibroblasts, thymic epithelial cells
  • Proinflammatory
  • Capillary leak
  • WBC recruitment and cytotoxicity
  • Cachexia in cancer
Transforming growth factor-β Most cells Antiinflammatory
Abbreviations:
IL: interleukin
IFN: interferon
NK: natural killer
Th2: type 2 T helper
TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF): tumor necrosis factor
WBC: white blood cell
Note: The list is not exhaustive, but important cytokines are included.

Microbial Killing

After pathogen recognition and recruitment of immune cells (with coordinated help from complements and cytokines), strategies are implemented to eliminate the microbes.

Pathogen elimination

  • Phagocytosis:
    • Phagocytes: macrophages, monocytes, neutrophils, dendritic cells
    • Attachment is either by recognition of PRR or mediated by opsonins. 
    • Engulfment of the pathogen in a vesicle follows
    • The phagocyte forms a pseudopod, which wraps around the pathogen and becomes a pinched-off membrane vesicle (phagosome). 
    • A phagolysosome is formed as the phagosome fuses with a lysosome.
    • Microbial killing mechanisms:
      • Acidification within the phagolysosome is bacteriostatic or bactericidal. 
      • ↓ pH activates pH-dependent, hydrolytic, lysosomal enzymes (digest the pathogen)
      • Antimicrobial peptides
      • Production of toxic nitrogen- and oxygen-derived species (respiratory or oxidative burst)
    • When the pathogen is destroyed, the phagocyte undergoes apoptosis (e.g., pus), or the waste is eliminated by exocytosis.
  • Other elimination strategies (if the pathogen is not engulfed):
    • Large pathogens (e.g., nematode) cannot be ingested:
      • Groups of cells (neutrophils, eosinophils, macrophages) surround the pathogen.
      • Defensins, lysosomal, and other toxic products are released (degranulation) to sufficiently eliminate the pathogen.
    • Immune cells kill the pathogens or infected cells (e.g., neutrophils release neutrophil extracellular traps (NETs), NK cells induce apoptosis).
Stages of phagocytosis

The stages of phagocytosis: engulfment of a pathogen, formation of a phagosome, digestion of the pathogenic particle in the phagolysosome, expulsion of undigested materials from the cell

Image: “The stages of phagocytosis” by Nina Parker et al. License: CC BY 4.0

Respiratory burst

  • Release of reactive oxygen species (ROS) from various cells (e.g., macrophages, neutrophils)
  • Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase complex reduces O₂ to an oxygen free radical (superoxide anion (O₂•)) and then to hydrogen peroxide (H₂O₂).
  • Neutrophils and monocytes (using myeloperoxidase) combine H₂O₂ with Cl → hypochlorite (HOCl•), which helps to destroy the bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview
  • Myeloperoxidase contains a heme pigment, which produces a green color in secretions (e.g., mucus and sputum) or pus.
Respiratory burst initiated by nadph oxidase adapted from 14

Respiratory burst initiated by the NADPH-oxidase complex:
The phagocyte NADPH-oxidase complex is activated, reducing O2 to an oxygen free radical (superoxide anion (O2)) and then to H2O2. Neutrophils and monocytes (using myeloperoxidase) combine H2O2 with Cl to produce hypochlorite (HOCl•), which helps destroy the bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview.

Image: “Respiratory burst initiated by NADPH oxidase complex” by Al Maruf A et al. License: CC BY 3.0

Clinical Relevance

  • Hereditary angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema: caused by deficiency or dysfunction of C1-INH, a protein regulating the classical pathway of complement activation. The condition is characterized by increased levels of bradykinin, which leads to enhanced vascular permeability. Symptoms include recurrent angioedemas (swelling of the face, lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue, and tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue). The GI tract may also be involved (nausea, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and vomiting). Diagnosis involves measurement of complement levels (low levels of C4 and decreased levels/functionality of C1-INH). Treatment includes purified, human C1-INH, kallikrein inhibitors, and bradykinin inhibitors. ACE inhibitors are contraindicated.
  • C1q deficiency: a rare disorder characterized by either absent or defective C1q protein. The disorder is caused by mutations in 1 of the 3 genes encoding C1q and has an autosomal-recessive inheritance. In most cases, the disease is associated with systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus). Other clinical manifestations include chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease, recurrent skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions, chronic infections, and alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia. Treatment depends on the symptoms. Production of C1q can be restored by allogeneic HSC transplantation. 
  • Terminal complement deficiencies (C5–C9): a genetic condition affecting MAC function. In the United States, deficiencies commonly found involve C5, C6, or C8. Because cell lysis still proceeds with C5–C8, deficiency of C9 causes less severe defects. The deficiency will appear as a low/undetectable CH50 titer. Individuals with terminal complement deficiency are at risk for recurrent Neisseria Neisseria Neisseria is a genus of bacteria commonly present on mucosal surfaces. Several species exist, but only 2 are pathogenic to humans: N. gonorrhoeae and N. meningitidis. Neisseria species are non-motile, gram-negative diplococci most commonly isolated on modified Thayer-Martin (MTM) agar. Neisseria infections.
  • Chronic granulomatous disease Chronic Granulomatous Disease Chronic granulomatous disease (CGD), as the name implies, is a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of defective phagocytic cells that are unable to produce bactericidal superoxide because of a defect in nicotinamide adenine dinucleotide phosphate (NADPH), the oxidase responsible for the respiratory burst in phagocytic leukocytes. Chronic Granulomatous Disease (CGD): a genetic condition characterized by granuloma formation and recurrent, severe bacterial and fungal infections. Defective NADPH oxidase (responsible for the respiratory burst) in neutrophils and macrophages leads to impaired phagocytosis. Infections commonly affect the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, lymph nodes, and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver. Dihydrorhodamine (DHR) 123 (a neutrophil function test) is abnormal and genotyping confirms the diagnosis. 
  • Systemic lupus erythematosus: a chronic, autoimmune-inflammatory condition causing immune-complex deposition in organs resulting in systemic manifestations. Features include a malar rash, nondestructive arthritis, nephritis, serositis, cytopenias, thromboembolic disease, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and/or psychosis. Diagnosis is based on clinical findings and tests (e.g., antinuclear antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus-specific antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins). Low C4 and C3 are noted in approximately 50% of cases because immune complexes activate the classical complement pathway. Management aims to control symptoms and prevent organ damage. Treatment options include corticosteroids, hydroxychloroquine, and immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants.

References

  1. C1q deficiency. (2016). Genetic and rare diseases information center. Retrieved July 9, 2021, from https://rarediseases.info.nih.gov/diseases/12958/c1q-deficiency
  2. Delves, P.J. (2020). Hereditary and acquired angioedema. MSD Manual. Merck & Co., Inc., Kenilworth, NJ, USA. Retrieved July 9, 2021, from https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic,-autoimmune,-and-other-hypersensitivity-disorders/hereditary-and-acquired-angioedema
  3. Haynes, B.F., & Soderberg, K.A., & Fauci, A.S. (2018). Introduction to the immune system. Jameson, J., & Fauci, A.S., & Kasper, D.L., & Hauser, S.L., & Longo, D.L., & Loscalzo, J. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192284326
  4. Johnston, R.B. An overview of the innate immune system. (2021). UptoDate. Retrieved July 7, 2021, from https://www.uptodate.com/contents/an-overview-of-the-innate-immune-system
  5. Liszewski, M.K., Atkinson, J.P. (2021). Inherited disorders of the complement system. UptoDate. Retrieved July 9, 2021, from https://www.uptodate.com/contents/inherited-disorders-of-the-complement-system
  6. Liszewski, M.K., Atkinson, J.P. (2021). Overview and clinical assessment of the complement system. Uptodate. Retrieved July 30, 2021, from https://www.uptodate.com/contents/overview-and-clinical-assessment-of-the-complement-system
  7. Mahlapuu, M., Håkansson, J., Ringstad, L., Björn, C. (2016). Antimicrobial Peptides: An Emerging Category of Therapeutic Agents. Front Cell Infect Microbiol, 27;6:194. https://pubmed.ncbi.nlm.nih.gov/28083516/ 
  8. Pier G.B. (2018). Molecular mechanisms of microbial pathogenesis. Jameson, J., & Fauci, A.S., & Kasper, D.L., & Hauser, S.L., & Longo, D.L., & Loscalzo, J.(Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=183880368
  9. Ryan K.J. (Ed.). (2017). Immune response to infection. Sherris Medical Microbiology, 7e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2268&sectionid=176081453
  10. Riedel, S., Hobden, J.A., Miller, S., Morse, S.A., Mietzner, T.A., Detrick, B., Mitchell, T.G., Sakanari, J.A., Hotez, P., Mejia, R. (Eds.). (2019). Immunology. Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2629&sectionid=217769996
  11. Smole U., Kratzer B., Pickl W.F. (2020). Soluble pattern recognition molecules: Guardians and regulators of homeostasis at airway mucosal surfaces. Eur J Immunol, 50(5):624-642. https://pubmed.ncbi.nlm.nih.gov/32246830/

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

0.0

()

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details