Cells of the Innate Immune System

The immune system is equipped with a varied repertoire of defense mechanisms against pathogens. Functionally, the immune system is differentiated into the innate and adaptive components. 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 (e.g., complement) that relay signals of a threat, and immune cells that help eliminate the microbe. Pathogen-associated molecular patterns (PAMPs) in microorganisms and damage-associated molecular patterns (DAMPs) from injured tissues are identified, and the appropriate cells are recruited. Involved cells include phagocytes and accessory cells. The offending pathogens are engulfed by phagocytes for destruction. In antigen-presenting cells (the most potent of which is the dendritic cell), parts of the pathogen material or peptides are transported to the cell surface. Through a unique antigen-loading mechanism specific to MHC I or II, the processed antigen peptides are then presented to the appropriate T cells, leading to T-cell activation. This interaction links innate immunity with adaptive immunity.

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Overview

Immune system

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

There are 2 lines of defense (that overlap):

  • Innate immunity (which is nonspecific) 
  • Adaptive immunity (based on specific antigen recognition):
    • Cell-mediated immunity: adaptive response in the cells/tissues involving the T cells
    • Humoral immunity: adaptive response in the fluids (humoral) involving B cells and immunoglobulins

Innate versus adaptive immunity

Table: Innate versus adaptive immunity
Innate immunityAdaptive immunity
GeneticsGermline encodedGene rearrangements involved in lymphocyte development
Immune responseNonspecificHighly specific
Timing of responseImmediate (minutes to hours)Develops over a longer period of time
Memory responseNoneResponds quickly upon recognition of antigen with memory response
Recognition of pathogenPattern recognition receptors (PRRs) such as TLRs recognize pathogen-associated molecular patterns (PAMPs)
  • Memory cells (T and B cells)
  • Activated B cells
Components
  • Anatomical barriers (e.g., skin)
  • Chemical and biologic barriers (e.g., gastric acid, vaginal flora)
  • Cells (e.g., granulocytes)
  • Secreted proteins:
    • Enzymes (e.g., lysozyme)
    • Other PRRs (e.g., antimicrobial peptides (AMPs)
    • Cytokines*
    • Complement* system
  • Cell-mediated immunity: T cells
  • Humoral immunity: B cells, immunoglobulins
*Mediators with roles in adaptive immunity

Components of the Innate Immune System

Innate immune response

  • Barriers:
    • 1st line of defense (mechanical, chemical, and biologic)
    • Define and line body surfaces
    • Secrete substances to remove and reduce pathogens
  • Microbe detection: The innate system uses the following to recognize the pathogen: 
    • Pattern recognition receptors (PRRs): proteins that distinguish self from foreign material, recognizing components specific to microbes:
      • Pathogen-associated molecular patterns (PAMPs): structures conserved among microbial species
      • Damage-associated molecular patterns (DAMPs), or alarmins: endogenous molecules released from damaged cells
    • According to the location of the interactions of the PRR and PAMPs, PRRs can be cell-associated (transmembrane or intracellular receptors):
      • TLRs
      • Retinoic acid–inducible gene (RIG) I–like receptors (RLRs)  
      • NOD-like receptors (NLRs)
      • C-type lectin receptors (CLRs) 
    • When the interaction occurs in body fluids (bloodstream and interstitial fluids), PRRs are secreted and circulating:
      • AMPs
      • Collectins
      • Lectins
      • Pentraxins
      • Antimicrobial oligosaccharides
  • A breach in the barriers triggers several processes → inflammation:
    • Occurs in response to infection or injury
    • Results in the cardinal signs (swelling, redness, heat, and 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 (assists in) eliminating the microbes)
      • Some PRRs (e.g., AMPs) are also involved in pathogen elimination.
  • Cellular response: Various cells (e.g., phagocytes) are recruited and participate in microbial killing.
  • The immune response is terminated when there is no longer a need (homeostasis).

Cells of the innate immune system

  • Many subsets of cells (that are involved in the innate response) develop from hematopoietic stem cells (HSCs) in the bone marrow (a primary lymphoid organ):
    • HSCs →  common myeloid progenitor → giving rise to:
      • Granulocytes: professional phagocytes (neutrophils, monocytes/macrophages), eosinophils, basophils, mast cells
      • Megakaryocytes → platelets
    • HSCs →  common lymphoid progenitor → giving rise to lymphocytes (which generally undergo activation and proliferation in the secondary lymphoid organs) such as:
      • B cells and T cells (adaptive immunity)
      • Natural killer (NK) cells (mostly innate immune response)
      • NK–T cells (bridge innate and adaptive immunity)
  • Individually, the cells have varying functions and targets in the immune response.
  • Among the crucial roles are:
    • Phagocytosis: Microbes or damaged particles are engulfed and digested.
    • Antigen presentation: performed by dendritic cells, macrophages, and B cells, facilitating antigen recognition by adaptive immunity
Stem cells differentiate into 2 pathways

Stem cells differentiate into 2 pathways:
Myeloid pathways produce erythrocytes, platelets, and cells of the innate immune response. Lymphoid pathways produce the cells of adaptive response and natural killer cells.

Image by Lecturio.

Professional Phagocytes

Phagocytes “eat” the foreign material, and help detect, clear, and repair damaged tissue, recognizing pathogens via PRRs or opsonization (by complement or immunoglobulins).

Neutrophils

  • Description:
    • 1st cells to be recruited into sites of infection
    • Chemokines secreted by immune or epithelial cells (at the sites) to attract neutrophils: 
      • N-formyl bacterial oligopeptide 
      • Complement-derived C5a 
      • Leukotriene B4 (secreted by numerous immune cells)
      • IL-8
  • Microbicidal functions: 
    • Phagocytosis and production of reactive oxygen species (respiratory burst) that are cytotoxic to bacterial pathogens
    • Neutrophil cytoplasmic granule proteases: neutrophil elastase and cathepsin G
    • Production of cytokines such as tumor necrosis factor (TNF) 
    • Use of extracellular strands of chromatin laced with antimicrobial proteins (neutrophil extracellular traps (NETs)) that catch and kill pathogens

Monocytes/macrophages

  • Description: Monocytes develop in the bone marrow and enter the circulation.
    • Some remain as monocytes, picking up and bringing antigens to the lymph nodes.
    • When monocytes migrate out of the circulation and go to tissues, monocytes differentiate into macrophages.
    • Macrophages are found in:
      • Lymph node, spleen, bone marrow, perivascular connective tissue, and serous cavities
      • In other tissues: lung (alveolar macrophages), liver (Kupffer cells), bone (osteoclasts), CNS (microglia cells), and synovium (type A lining cells)
    • Also differentiate into dendritic cells during inflammation
  • Functions:
    • Respond briskly to pathogens, facilitated by high density of surface PRRs
    • Use NO to kill pathogens, and also produce large amounts of cytokines
    • Antigen presentation to lymphocytes (stimulating the adaptive immune response)
    • Play a role in iron homeostasis
Development of monocyte

Monocyte development starts from hematopoietic stem cells (HSCs) and progresses through stages to the colony-forming unit granulocyte-macrophage (CFU-GM):
The 1st monocyte precursor is the monoblast, which has a round or oval nucleus.
The promonocyte follows and has a convoluted nucleus.
The monocyte arises with an indented nucleus and is released from the bone marrow to become a macrophage in the tissues.

Image by Lecturio. License: CC BY-NC-SA 4.0

Dendritic cells

  • Description:
    • Most potent antigen-presenting cells
    • Name derived from presence of dendritic (branching) extensions
    • Arise from bone marrow
    • Links innate and adaptive immunity by antigen presentation and release chemokines, which attract T cells and B cells when a pathogen is detected.
  • Types of dendritic cells:
    • Myeloid dendritic cells:
      • Also called conventional dendritic cells
      • Can be interstitial dendritic cells (in blood and interstices of lung, heart, kidney) or Langerhans dendritic cells
    • Plasmacytoid dendritic cells: 
      • Lymphoid lineage
      • Plasmacytoid dendritic cells primarily reside in and recirculate through lymphoid organs.
      • Inefficient antigen-presenting cells but massively produce type I interferon (IFN) when viral infections occur
  • Functions (vary with maturation):
    • Phagocytosis of microbes, molecules from damaged tissue, self-antigens, tumors
    • Subsequent steps lead to maturation (expression of MHC II and costimulatory molecules, PRRs, with up-regulation of cytokine receptors)
    • Become more antigen-specific with maturity and participate in the adaptive immune response
    • Once mature, dendritic cells present antigens to T cells, which then proliferate.
    • Positive feedback: effector T lymphocytes secrete IFN‒ɣ → make the dendritic cells produce ↑ IL-12  and ↑ microbicidal activity of macrophages
Dendritic cells releasing IL-12

Dendritic cells release IL-12, which activates CD4 Th1 cells. These Th1 cells produce IL-2, stimulating production of more Th1 T-cell subsets. Th1 cells also release IFN-γ, which activates macrophages and activates fibroblasts to cause angiogenesis and fibrosis. If these macrophages are persistently stimulated by pathogens such as ,Mycobacterium and Schistosoma, granulomas are formed.

Image by Lecturio.

Dendritic cells versus follicular dendritic cells

It is important to note that follicular dendritic cells are completely unrelated to dendritic cells in lineage and function. 

Follicular dendritic cells:

  • Concentrated in the secondary lymphoid organs where B-cell activation occurs
  • Trap antigens on their surfaces that are then bound by the B-cell receptors of B cells (B-cell activation)
Table: Differences between dendritic cells and follicular dendritic cells
Dendritic cellsFollicular dendritic cells
OriginDerived from hematopoietic stem cellsDerived from mesenchymal stem cells
SitesPresent throughout the bodyPresent only in germinal centers of secondary lymphoid tissues
MHC class and costimulatory moleculesPossess MHC II and costimulatory (e.g., B7) moleculesLack MHC II and costimulatory molecules
Functions
  • Activate helper T cells
  • Initially phagocytic
  • Do not activate helper T cells
  • Specialized in presenting antigen to B cells
  • Never phagocytic

Phagocytosis

  • Attachment is either via recognition of the PRR or mediated by opsonins (proteins that bind/tag pathogens and make them palatable for phagocytes).
    • Engulfment of the pathogen in a vesicle follows.                               
    • The phagocyte forms a pseudopod that wraps around the pathogen, and this becomes a pinched-off membrane vesicle called a phagosome. 
    • A phagolysosome is formed as the phagosome fuses with a lysosome.
    • In the compartment, the pathogen is eliminated by different microbial killing mechanisms.
  • When the pathogen is destroyed, the phagocyte undergoes apoptosis (e.g., seen in pus) or the waste is eliminated by exocytosis.
  • In antigen-presenting cells, parts of the pathogen material or peptides are transported to the cell surface for antigen presentation.

Accessory Cells

Eosinophils

  • Description:
    • Recognized by their prominent eosinophilic cytoplasmic granules
    • Located primarily in the lamina propria of the GI tract
  • Functions:
    • Released extracellular traps contain eosinophil granules (that secrete their contents, including the cytotoxic major basic protein) when stimulated 
    • Have cytotoxic effect against helminths and other parasites
    • Also have extensive antibacterial and antiviral activity
    • Mediate eosinophilic GI diseases

Basophils

  • Description:
    • Circulating leukocytes; not found in tissues
    • Express high-affinity receptors for IgE
  • Functions:
    • With IgE receptors, basophils participate in immediate hypersensitivity types of allergic immune response
    • Provide resistance against helminths  
    • Activities are mediated by histamine, cathelicidin, and other mediators
    • Produce IL-4 and IL-13, which promote Th2 response
Cells of the Innate Immune System

Eosinophil and basophil
Both are granulocytes, with eosinophils possessing a bilobed nucleus and dark pink granules and basophils having a bilobed or trilobed nucleus, and dark blue granules.

Image: “Granulocytes can be distinguished by the number of lobes in their nuclei and the staining properties of their granules.” by Parker N et al. License: CC BY 4.0, cropped by Lecturio.

Mast cells

  • Description:
    • Morphologically similar to basophils
    • Found in large numbers in interstitial tissues
    • Express: 
      • TLRs 1, 2, 4, and 6 (for the complement anaphylatoxin C5a)
      • Receptors for mannose-binding lectin (MBL)
  • Functions:
    • Participate in allergic responses and have antimicrobial and antiprotozoan functions
    • Release upon activation:
      • TNF-ɑ 
      • IL-8 
      • Inflammatory mediators (heparin, histamine, platelet-activating factor, leukotrienes)
      • Proteases (e.g., tryptase, chymase)
      • Antimicrobial peptides such as cathelicidin and defensins

Natural killer cells

  • Description:
    • Lymphoid cells that do not express T- or B-cell receptors
    • Express a number of activating and inhibitory receptors 
    • Have granules with perforins and granzymes
    • Become senescent with age and obesity
  • Functions:
    • Activating receptors are key to the “killer function” in viral infections and malignant tumors, effecting pathogen death through:
      • Fas–Fas ligand caspase pathway
      • Granzyme/perforin pathway
    • Avoid attacking host cells through recognition of MHC I molecules expressed in all healthy host cells
  • NK–T cells: have both T-cell and NK-cell surface markers and functions

Platelets

  • Description: circulating small cell fragments (bud off from megakaryocytes)
  • Functions:
    • Express PRRs
    • Produce cytokines
    • Recruit leukocytes to sites of injury or inflammation
    • Megakaryocytes secrete IFN-α and IFN-β

Antigen Presentation

Antigen-presenting cells (such as dendritic cells and macrophages) detect, process, and present the antigens to T cells, allowing adaptive immunity to recognize and mount a response every time the pathogen is encountered (immunologic memory).

Major histocompatibility complex (MHC)

  • Proteins found in antigen-presenting (and other) cells that are encoded by the HLA genes, located on chromosome 6
  • Principal function: present the antigen to adaptive immune system (T cells)
  • Represents the interaction between the innate (e.g., antigen-presenting cells) and adaptive immunity (T cells)
  • MHC classified as:
    • MHC I: 
      • Found on all nucleated cells
      • When a cell has an intracellular pathogen (e.g., virus), MHC brings endogenous antigens to the surface, presenting them to CD8+ T cells. 
      • Structure: 1 short and 1 long chain (ɑ chain with 3 domains: ɑ1,  ɑ2,  ɑ3), associated with the β₂-microglobulin
    • MHC II: 
      • Found only on certain immune cells (APCs)
      • Present exogenous antigens (e.g., bacterial proteins) to CD4+ T cells
      • Structure: 2 ɑ and 2 β chains of equal length
Cells of the Innate Immune System

Structures of MHC I and MHC II:
MHC I has 1 short and 1 long chain (ɑ chain with 3 domains: ɑ1, ɑ2, and ɑ3), associated with the β₂-microglobulin. MHC II has 2 ɑ and 2 β chains. The peptide antigen goes to the antigen-binding cleft.

Image: “MHC I are found on all nucleated body cells, and MHC II are found on macrophages, dendritic cells, and B cells (along with MHC I).” by Parker N et al. License: CC BY 4.0

Routes of antigen presentation

  • MHC I:
    • Proteasomes degrade proteins (within the cell) into peptides. 
    • Peptide fragments are transported (via transporter associated with antigen processing) to the ER.
    • In the ER, aminopeptidases further trim the peptides.
    • Antigen peptides are then loaded onto the MHC I molecules → to the Golgi apparatus for posttranslational modification
    • Then the complexes are transported to the cell surface, where they are presented to CD8+ T cells. 
  • MHC II:
    • Antigen-presenting cells take up extracellular antigens and are engulfed within phagosomes. 
    • Phagosomes fuse with lysosomes (containing proteolytic enzymes that cleave the phagocytosed proteins into small peptides).
    • In the ER:
      • Newly synthesized MHC II molecules have the invariant chain, which binds the antigen-binding cleft.
      • With the site occluded, other ER-resident peptides cannot bind the cleft. 
      • From the ER, the invariant chain directs the MHC II complex to the acidified endosome (where antigen peptides are). 
      • In the endosome, the invariant chain is released → peptides are loaded onto MHC II complexes (chaperoned by HLA-DM) 
      • Peptide-loaded MHC II complexes are transported to the cell surface, allowing antigen presentation to CD4+ T cells.

MHC I versus MHC II

Table: MHC I versus MHC II
MHC IMHC II
LociHLA-A, HLA-B, HLA-CHLA-DP, HLA-DQ, HLA-DR
BindingCD8 T cellCD4 T cell
DistributionAll nucleated cells (none on RBCs)Antigen-presenting cells
RolePresent endogenous antigens to CD8+ T cells (cytolytic)Present exogenous antigens to CD4+ T cells
Structure
  • 1 long chain
  • 1 short chain
2 chains of equal length (2 ɑ, 2 β)
Associated proteinβ₂-microglobulinInvariant chain
Antigen loadingLoading of antigen peptide onto MHC I in ER (delivered via TAP)Loading of antigen peptide onto MHC II in the acidified phagolysosome after release of invariant chain
TAP: transporter associated with antigen processing

Related diseases

The HLA region encodes several molecules that perform key functions in the immune system. There is a robust association between the HLA region and several diseases.

Table: HLA subtypes and associated conditions
HLA subtypeCondition(s)Mnemonics
A3HemochromatosisHA3mochromatosis
Fe3 (iron = hemochromatosis), A3
B8
  • Addison’s disease
  • Myasthenia gravis
  • Graves’ disease
Don’t B l8, Dr. Addison, or you’ll send my patient to the grave!
B27
  • Psoriatic arthritis
  • Ankylosing spondylitis
  • Inflammatory bowel disease-associated arthritis
  • Reactive arthritis (seronegative arthropathies)
PAIR
CPsoriasisC-riasis
DQ2/DQ8Celiac diseaseI 8 2 much gluten at Dairy Queen (DQ2/8; gluten = celiac disease)
DR2
  • Multiple sclerosis
  • Hay fever
  • Goodpasture syndrome
  • Systemic lupus erythematosus (SLE)
  • Drive 2 multiple hay pastureS
  • 2-3, SLE
DR3
  • SLE
  • Diabetes type 1
  • Graves’ disease
  • Hashimoto’s thyroiditis
  • Addison’s disease
  • 2-3, SLE
  • 3-4, sugar (diabetes)
  • Dr. Hashimoto is odd (odd numbers 3, 5)
DR4
  • Diabetes type 1
  • Rheumatoid arthritis
  • Addison disease
  • Add rheumatoid arthritis, and you’re on all 4s (joints)!
  • 3-4, sugar (diabetes)
DR5Hashimoto’s thyroiditisDr. Hashimoto is odd (odd numbers 3, 5)
DR7Steroid-responsive nephrotic syndrome7, “pee in heaven” (nephrotic)

Clinical Relevance

  • Severe congenital neutropenia (SCN): condition with a deficiency of neutrophils. Severe congenital neutropenia manifests in infancy with life-threatening bacterial infections. Kostmann disease (SCN3) has an autosomal recessive inheritance pattern, whereas the most common subtype (SCN1) shows autosomal dominant inheritance. The most common cause is a mutation in the ELANE gene. The treatment proven to be effective is the administration of granulocyte colony-stimulating factor, which elevates the decreased neutrophil count.
  • Chediak-Higashi syndrome (CHS): autosomal recessive disorder that is caused by mutations affecting a lysosomal trafficking regulator protein. This protein plays a crucial role in the inability of neutrophils to kill phagocytosed microbes. NK-cell hyporesponsiveness is also noted in some cases. Individuals with CHS exhibit recurrent pyogenic infections, easy bleeding and bruising, and neurologic manifestations. 
  • Chronic granulomatous disease (CGD): genetic condition characterized by recurrent severe bacterial and fungal infections, and granuloma formation. Defective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (responsible for the respiratory burst) in neutrophils and macrophages leads to impaired phagocytosis. Infections commonly affect the lung, skin, lymph nodes, and liver. A neutrophil function test, dihydrorhodamine (DHR) 123, is abnormal, and genotyping confirms the diagnosis.

References

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