Cells of the Innate Immune System

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

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 patterns (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

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

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 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)

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

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

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

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.

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 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.