Adaptive Immune Response

Immune responses against pathogens are divided into the innate and adaptive immune response systems. The adaptive immune response, also called the acquired immune system, consists of 2 main mechanisms: the humoral- and cellular-mediated immune responses. Humoral immunity is mediated through B cells (producing antibodies), whereas cell-mediated immunity involves T cells, and this response is activated when the innate immune system fails to control an infection. As the 2nd line of defense, the adaptive immune system is slower and responds over a longer period of time, but the effect generally leads to specific immunological memory. The 2 important characteristics of adaptive response are specificity (with antigen recognition) and memory (immune response mounted with reinfection).

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Overview

Immune system

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

2 lines of defense (that overlap):

  • Innate immunity (which is nonspecific) 
  • Adaptive (acquired) immunity (based on specific antigen recognition):
    • Cell-mediated immunity: adaptive response in the 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 the 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 Igs

Innate vs adaptive immunity

Table: Innate vs. 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 With memory response, which responds quickly upon recognition of antigen (Ag)
Recognition of pathogen Pattern recognition receptors (PRRs) such as 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, Igs
*These mediators also have roles in adaptive immunity.

Components of the Adaptive Immune System

Adaptive immunity

The adaptive immune response is divided into the humoral- and cell-mediated immune systems. 

  • The primary cells of the adaptive immune system are 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 (B 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).
    • 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 play an important role in the humoral immune response.
    • 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 are primarily involved in the cell-mediated response.
    • These cells undergo different stages:
      • Naive cells are cells that have not yet encountered their Ag.
      • Effector cells have been activated by a matching Ag.
      • Memory cells are cells that have outlived a previous infection.

Cell-mediated immunity

  • Primary effectors: 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
  • Other components that are also a part of the innate immunity:
    • Ag-presenting cells: such as dendritic cells (most potent Ag-presenting cell), 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
    • Cytokines: soluble proteins released by different cells, which play overlapping roles in both innate and adaptive immunity 
  • Overview:
    • An Ag-presenting cell is an immune cell that detects and informs the adaptive immune response about an infection or invasion by activating 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.
    • 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, in turn, activate the 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, producing Igs.
  • The Cell-mediated response occurs in the cells/tissues (intracellular infections or aberrant cells such as tumors).

Humoral adaptive immunity Humoral Adaptive Immunity Humoral adaptive immunity is an integral part of the adaptive immune system, which mounts a highly specific defense against pathogens but takes a longer time to respond (compared to the innate immune system). Humoral immunity is the arm of the immune system protecting the extracellular fluids of the lymphatics (lymph), interstitium, and circulatory system (plasma) from microbial contamination mediated through soluble molecules. Humoral Adaptive Immunity

  • Antibody-mediated immunity
  • Composed of 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 and 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
    • 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 encountered by the Ag respond by activation, proliferation, and differentiation, generating 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.
    • The 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 later differentiate into plasma cells and memory cells.
    • The memory cells lead to long-lasting immunity and enable rapid immunologic responses upon subsequent exposure to the Ag.
  • Humoral immunity protects the extracellular fluids (ECFs) (“humoral”) of the lymphatics (lymph), interstitium, and circulatory system (plasma) from microbial contamination.

Cell-Mediated Immunity Activation

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 antigen presentation

  • 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 are derived from common lymphoid progenitors (CLPs).
  • Unlike 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, these cells from 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 migrate to the thymus to complete T cell development.
  • For proliferation and activation to occur, naive mature 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 (which have either cluster of differentiation (CD) molecules 4 or 8 (CD4 or CD8)) have to interact with a foreign antigen.
  • Thus, they circulate in the blood and go to the secondary lymphoid tissues.
  • These secondary lymphoid organs (e.g., lymph nodes) filter antigenic material, allowing the naive mature 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:
    • To sample the Ags to get activated
    • To interact with Ag-presenting cells such as macrophages or dendritic cells.
      • Ag-presenting cells phagocytose the pathogen and digest the Ag into fragments.
      • Peptide fragments are then loaded onto MHC class I or MHC class II molecules.
      • Once processed, these are transported to the cell surface for the presentation of Ag.
    • The Ag presented on MHCs are recognized by 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 using a T cell receptor (TCR) specific to the antigen.
      • CD4 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 helper cells (Ths)) bind only to Ag–MHC II complexes.
      • CD8 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 (cytotoxic 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 (Tcs)) bind only to Ag–MHC I complexes.
  • T cell activation follows (requiring 2 signals to get activated), with 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 becoming effector 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 (functioning in cell-mediated immunity).
Routes of antigen presentation mhc i and ii molecules

Routes of antigen presentation by MHC class I and II molecules:
In class I Ag presentation (left), proteasomes degrade endogenous Ags or proteins (within the cell) into peptides. Peptide fragments are transported (via transporter associated with antigen processing (TAP)) to the ER, where they are further trimmed by aminopeptidases and loaded onto the MHC class I molecule. The MHC class I–loaded complexes go to the Golgi apparatus for posttranslational modification. Then the complexes are transported to the cell surface, where they are presented to CD8+ 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. In class II Ag presentation (right), extracellular/exogenous Ags are taken up within phagosomes by Ag-presenting cells. The phagosomes then fuse with proteolytic enzyme-filled lysosomes. This results in the breakdown of phagocytosed proteins into small peptides. Meanwhile, in the ER, new MHC class II molecules are synthesized. These molecules have the invariant chain (pink structure in the right image, marked “Ii”), which binds the Ag-binding cleft. With the cleft occluded (by the invariant chain), ER-resident peptides cannot bind. The invariant chain directs the MHC II complex to the acidified endosome (where Ag peptides are) as it exits from the ER. When MHC II complexes are delivered to the endosome, the invariant chain is released, allowing loading of Ag peptides (chaperoned by a protein, HLA- DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus) onto the MHC class II molecules. Once loaded, the formed Ag peptide–MHC class II complexes are brought to the cell surface, ready to present the Ag to CD4+ 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.
Ii: MHC class II–associated invariant chain
MIIC: MHC class II compartment

Image by Lecturio.

Activated 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

  • CD4+ 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
    • With effector activities: Th1, Th2, Th9, Th17, Th22, T follicular helper (Tfh) cells 
    • With regulatory activities: regulatory 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 (Treg)
  • Cytokines, signaling proteins important for immune cell growth, stimulate 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, at the same time, are secreted by 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.

Description of CD4+ T cell subsets

Table: Description of CD4+ T cell subsets
CD4+ 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 Stimulated by Cytokines produced Functions Role in disease
Th1 IL-12, IFN-γ IFN-γ, 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), IL-2
  • Activate macrophages
  • Activate Tcs
  • Eradicate intracellular organisms
  • Proinflammatory
  • 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
Th2 IL-2, IL-4 IL-4, IL-5, IL-6, IL-9, IL-10, IL-13
  • Activate eosinophils, ↑ IgE
  • Activate mast cells
  • Parasitic infections (e.g., helminths)
  • Allergic conditions
Th17 IL-1, IL-6, IL-23, TGF-β IL-17, IL-21, IL-22 Promote neutrophilic 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
  • Extracellular 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
  • Neutrophil-predominant asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma
  • 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
Tfh IL-6 IL-4, IL-21 Facilitate B cell activation and maturation Antibody production
Treg TGF-β, IL-2 TGF-β, IL-10, IL-35
  • Suppress immune response
  • Promote self-tolerance
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, allergy, 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

Other CD4+ T cell subsets

  • Th3
    • Important in mucosal tolerance induction 
    • Promote formation and maintenance of induced Treg cells
  • Th9 and Th22 are recently discovered.
    • Th9: 
      • Stimulated by IL-4, TGF-β
      • Important in antitumor immunity, allergy, and autoimmune disease
    • Th22:
      • Produces IL-22 (like Th17 cells)
      • The secretion of IL-22 with IL-17 produces proinflammatory effects (such as in psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis).
      • Involved in mucosal immunity

CD8+ 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

  • Tcs or cytolytic 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
  • Requires cytokine (IL-2) stimulation (from Th1 cells) to be activated, then leaves the secondary lymphoid organ, circulating in search of targets
  • Produce cytokines IFNγ, 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)-α, and 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)
  • 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 factor: RUNX3
  • Functions include killing of:
    • Pathogens
    • Infected cells
    • Tumor cells
    • Allografts

Humoral Immunity Activation

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

  • 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 arise from the common lymphoid progenitor (CLP). 
  • In stages, 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 develop 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 and undergo activation to perform humoral immune response.
  • A mature naive B cell with a B cell receptor (BCR):
    • Exits 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, migrating to secondary lymphoid organs
    • Expresses IgM and IgD once within the secondary lymphoid tissues
B-cell receptor

B cell receptor (BCR):
Consists of the Ig molecule and signaling molecule.
The membrane-bound Ig is anchored to the cell surface. The Ig contains 2 identical heavy chains and 2 identical light chains, linked by a disulfide bridge.

Image: “Figure 42 02 06” by CNX OpenStax. License: CC BY 4.0, edited by Lecturio.

B cell activation

  • Steps (in detail) are needed for the B cell to function.
  • Activation can be:
    • T cell dependent
      • 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 bind and engulf foreign Ags via their BCRs (functioning as Ag-presenting cells) and then display Ags via MHC II molecules to 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 encounter activated CD4+ Tfh cells (specialized CD4 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).
      • The MHC II–Ag complex is recognized by Tfh 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 are activated → B cell proliferation
    • T cell independent
      • Activation does not always need the help of 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.
      • Some Ags, like the polysaccharides of a bacterial cell (e.g., Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae and Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus influenzae), can directly stimulate 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.
      • Short-lived responses, with mostly IgM production (no memory)
  • To produce a functional differentiated B cell after activation by an Ag, processes that take place include:
    • Proliferation
    • Affinity maturation:
      • Fine-tuning of the antibody affinity to the Ag
      • Achieved by somatic hypermutation (programmed mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations involving Ig heavy and light chain genes)
      • Produces BCR with enhanced ability to recognize and bind Ag
    • Class switching:
      • Heavy chain determines the Ig class (IgM, IgG, IgE, IgA, IgD).
      • Influenced by cytokines
      • Accomplished by genetic rearrangement of segments encoding the constant region, whereas the variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables region is not changed
    • Differentiation into plasma or memory cell
B cell activation in the humoral immune response

The image shows B cell activation in the humoral immune response producing the 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.

Image: “B cell activation” by Fred the Oyster. License: CC0 1.0, edited by Lecturio.

Immunological Memory

A memory cell is an Ag-specific B or T lymphocyte that produces a strong immune response after re-exposure to the same pathogen. Both memory B 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 express the surface marker CD27.

Memory 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

  • React to antigenic stimulation (in response to reinfection)
  • Generate plasma cells that have high affinity 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 (particularly IgG) in secondary immune responses

Memory 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

  • Can be either CD4+ or CD8+
  • These cells live for many years after their initial differentiation and maturation, mounting an immune response years after initial exposure.
  • Following initial exposure to Ags, some 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 develop into memory cells:
    • These cells initially reside within lymphoid tissues (central memory 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 memory cells then take residence in peripheral tissues (effector memory cells).
    • Following reinfection by the same antigen, they become effector 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.
Diagram of primary and secondary immune responses

Primary and secondary immune responses:
In a primary immune response, naive 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 are stimulated by antigen (Ag). B cell activation and then differentiation into antibody-secreting cells occur. The 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 are specific for the eliciting Ag. Then IgM production is followed by IgG. While there is an immune response, the production is low level. In the secondary immune response, the same Ag stimulates memory 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 the production of greater quantities of 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 that are produced in the primary response. The production and release of IgG also occurs earlier.

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Clinical Relevance

  • X-linked agammaglobulinemia X-linked agammaglobulinemia X-linked agammaglobulinemia, also known as Bruton's agammaglobulinemia or Bruton's disease, is a rare, recessive genetic disorder characterized by the improper development of B cells, leading to a lack of mature B cells capable of responding to stimulation by cell-mediated immune responses or certain antigen-presenting cells. X-linked Agammaglobulinemia (XLA): results from mutations in the X chromosome gene encoding for Bruton tyrosine kinase (BTK), which is essential for B cell development and maturation. The disease is characterized by an absence 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 recurrent infections, primarily by encapsulated 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 viruses, involving 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, sinuses, and 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 as well as the CNS. Treatment involves administration of Ig.
  • Common variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables immunodeficiency (CVID): also known as humoral immunodeficiency, CVID is a disorder of the immune system characterized by reduced serum levels of IgG, IgA, and IgM. The underlying causes of CVID are largely unknown. Patients with CVID are prone to infections in the GI tract and the upper and lower respiratory tracts (URTI and LRTI). Common variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables immunodeficiency is also associated with a higher risk of developing autoimmune disorders, granulomatous diseases, and malignancy. The treatment is Ig replacement therapy.
  • Chronic mucocutaneous candidiasis Candidiasis 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 (CMCC): autoimmune syndrome with features including chronic, noninvasive 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 infections of the 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, nails, and mucous membranes. The condition is associated with autoimmune manifestations (most commonly endocrinopathies). Hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism is the most common endocrine abnormality, occurring in 30% of patients. Adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease (AI) occurs in > 60% of cases by the age of 15. Chronic mucocutaneous candidiasis Candidiasis 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 is due to genetic defects in the immune system, including those affecting the autoimmune regulator (AIRE), which is important in the negative selection of 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 the interleukin (IL) 17 pathway, among others.
  • Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX): a disease caused by mutations in the gene for the transcription factor FOXP3. The defining feature is regulatory T cell impairment, manifesting as autoimmune disease with allergic 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. The disease typically presents in male infants with a triad of enteropathy, dermatitis, and autoimmune endocrinopathy (usually type 1 diabetes or thyroiditis Thyroiditis Thyroiditis is a catchall term used to describe a variety of conditions that have inflammation of the thyroid gland in common. It includes pathologies that cause an acute illness with severe thyroid pain (e.g., subacute thyroiditis and infectious thyroiditis) as well as conditions in which there is no clinically evident inflammation and the manifestations primarily reflect thyroid dysfunction or a goiter (e.g., painless thyroiditis and fibrous Riedel's thyroiditis). Thyroiditis). Diagnosis is by mutational analysis of the FOXP3 gene. Hematopoietic cell transplantation is the only curative therapy available.
  • Adult T cell leukemia/lymphoma: a rare but often aggressive mature T cell malignancy caused by chronic infection of CD4+ 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 with the human T-lymphotropic 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, type I (HTLV-I). The general presentation is widespread involvement of lymph nodes, peripheral blood, and/or 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. The most characteristic features seen in the peripheral blood are “clover leaf” or “flower” cells (cells with bizarre hyperlobulated nuclei). Diagnosis is based on clinical presentation, morphologic and immunophenotypic changes of the malignant cells, and confirmed HTLV-I infection. The treatment includes antiviral agents, monoclonal antibody therapy, chemotherapy, and allogeneic stem cell transplantation.

References

  1. Chaplin, DD. (2010). Overview of the immune response. Journal of Allergy and Clinical Immunology, 125(2), S3–S23. https://doi.org/10.1016/j.jaci.2009.12.980
  2. El-Sayed, ZA, Abramova, I, Aldave, JC, Al-Herz, W, Bezrodnik, L, Boukari, R, Bousfiha, AA, et al. (2019). X-linked agammaglobulinemia (XLA): Phenotype, diagnosis, and therapeutic challenges around the world. World Allergy Organization Journal, 12(3), 100018. https://doi.org/10.1016/j.waojou.2019.100018
  3. Fischer, A. (2000). Severe combined immunodeficiencies (SCID). Clinical and Experimental Immunology, 122(2), 143–149. https://doi.org/10.1046/j.1365-2249.2000.01359.x
  4. Grubbs, H, & Kahwaji, CI. (2021) Physiology, active immunity. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513280/

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