Innate Immunity And The Complement System

Anatomical Barriers

These are colonized by natural microbiota. They take up space which could be occupied by invaders, secrete their own anti-microbial proteins, and stimulate natural antibodies. These organisms can cause problems in immunocompromised patients, if colonized in an abnormal location, or if stimulating an auto-immune reaction.

Skin (epidermis)

Your meat suit. It also has lamellar bodies which secrete beta-defensin and calthelicidins (anti-microbial).

Lungs (bronchial and respiratory epithelium)

Has a mucosal layer and ciliated cells. The mucus traps particulate matter/pathogens and the cilia helps moves the debis out via cough.

Patients with cystic fibrosis have thicker/dryer mucus making it more difficult to clear their lungs and making them more susceptible to infection.

Gut epithelium

Had mucosal layer and ciliated cells. Physically move out pathogens via peristalsis. Paneth cells release alpha-defensin (anti-microbial).

Others: Eyes, Nose, Oral Cavity

Anti-Microbial Proteins/Peptides

Assist by disrupting the membranes of pathogens.

Lysozyme

Found in tears and saliva. Secreted by phagocytes and Paneth cells (in the gut). Targets gram positive bacteria by degrading peptidoglycan. Gram (-) bacteria has a secondary outer membrane protecting the peptidoglycan.

This exposes the lipid bilayer for secretory phospholipase A2 to destroy the membrane.

Defensin, calthecidins, lecticidens, histidins

Targets bacteria, fungi, and some viruses. Synthesized as pro-peptides which are cleaved to be activated. The mature form is amphipathic (negative and positive charges). It attaches to the microbial membrane to form pores.

Locations

Skin (lamellar bodies): Beta-defensin and calthelicidins
Gut (Paneth cells): Alpha-defensin, calthecidins, lecticidens
Oral cavity: Histidins (specifically for fungi)

Complement System

Found in the blood (humoral immunity) and responds to MAMPs on pathogens, either destroying the pathogen of recruiting/assisting other immune cells. Generally, when proteins are activated in this cascade, the cleaved (B form) binds while the original (A form) goes away.

C3 Convertase

Classical Pathway

In which the C1 binding complex binds pathogens with these features: IgM/IgG antibodies (low affinity), c-reactive proteins, or MAMPs (like lipoteichoic acid). It has q, r, and s subunits.

C1Q initiates cascade: C1r → C1s→ C4 → C4b
C4b recruits C2
C1s cleaves C2 → C2a (serine protease) and C2b
C4b + C2a → C3 convertase

Lectin Pathway

In which either Mannose Binding Lectins (MBLs) bind to mannose on microbial cell walls or Ficolins bind to other carbohydrates.

MASP1,2,3 (MBL-associated-serine-proteases) binds to MBL/Ficolins on the cell wall
MASP 1 → MASP 2 → C4 → C4b
Proceeds as the classical pathway

Alternative Pathway

Makes an activated C3 convertase before binding to pathogens.

C3 spontaneously hydrolyzes and binds to Factor B
Factor B cleaves Factor D, forming C3 convertase
C3 convertase cleaves C3 → C3b (effector complement) and C3a (inflammation)

The C3b must bind to microbial surfaces immediately or else become inactivated.

Outcomes

Membrane attack complex (MAC)

C3 convertase + C3b → C5 convertase
C5 convertase cleaves C5 → C5b
C5b + C6-9 → MAC

MAC punches holes into sides of the cell membrane of microbes.

Opsonization

Most important effect. Will optimize phagocytosis. Microbes covered in C3B are more easily detected by phagocytes. C3B is more efficient at killing pathogens than MAC, but it requires recruitment of additional cells.

Inflammation

C3a, C4a, and C5a all increase inflammation. This improves vascular permeability and induces Mast Cell degranulation (releasing histamines and TNFa). As a systematic activation of this cascade can lead to anaphylactic shock, these subunits are called anaphylatoxins.

Regulation

C1 inhibitor breaks up C1r/C1s (stopping classical pathway) and C3 convertase/MAC formation is inactivated. Pathogens can avoid the complement system by attracting Factor H/I (inactivators).

Clinical pearls

The following are diseases resulting from deficits in each complement system component. These increases susceptibility to Neisseria and, in the case of C3, S. pneumoniae.

C1, C2, C4 deficit (childhood)

Recurrent otitis and sinusitis. Systemic infection in 20% of individuals.

C3 deficit (childhood)

Severe case presentation. Recurrent otitis and sinusitis. Severe systemic infection in 70% of individuals. Reinfection with same organism.

MAC deficit (teens)

Increased susceptibility to Neisseria meningitidis. Reinfection with same organism.

C1 inhibitor deficit (childhood-adolescence)

Antiedema without urticaria (swelling without redness) in response to trauma. Hereditary or acquired. Recurrent, asymmetric swelling of face, lips, or tongue.

Innate Cellular Response

Myeloid Lineage

Macrophages

For more on macrophages in inflammation, see here: Inflammation and Repair > Macrophages

Phagocytose pathogens and kill them using oxidative/respiratory bursts using NADPH oxidase. An NBT reduction test can be used to test for activity of the respiratory burst.

They recognize microbes via Toll-Like Receptors (TLRs). They bind to MAMPs/DAMPs. Cell surface TLRs recognize microbial cell wall features, while endosome TLRs recognize digested pathogen features. Basis for adjuvant.

TLR + MAMP → degrade IkB → NFkB enters the nucleus → turns on pro-inflammatory/antiviral cytokine genes specific to the pathogen

They will also secrete cytokines/chemokines to increase swelling and recruit helper cells.

IL1b, TNFa, IL6: Vasodilation, swelling
IL6: Stimulates liver to produce induced phase proteins. C-reactive protein (opsonization), fibrinogen (clotting), and MBL (complement system).
IL8, CXCL8: Recruits neutrophils, basophils, T cells
IL12: Activates NK cells and induces Th1 differentiation
GCSF: Increases neutrophil production

Finally, in response to viruses, macrophages will also produce interferons which interfere with viral replication and infection, focuses the anti-viral attack for dendritic cells, macrophages, and NK cells.

Clinical pearl: Chronic granulomatous disease

Deficiency in NADPH oxidase means macrophages cannot kill pathogens. This results in chronic infections and granulomas which come from macrophages which have phagocytosed pathogens but cannot kill them.

For more, see here: Immunodeficiency Diseases > Defects of oxidative metabolism

Neutrophils

Phagocytose and kill pathogens via respiratory bursts. Attracted to infection site via chemokines (IL8). Can also degranulate and release pathogen-killing enzymes.

Dendritic cells

See here: T Cell Mediated Immunity > Dendritic Cells (DCs)

Eosinophils and Basophils

Kills parasites by recognizing IgE, IgA, or IgG and degranulating reactive oxygen species (ROSs). They also increase collagen deposition to form a granuloma around parasitic infection.

Involved in asthma, allergy, and hypersensitivity.

Mast cells

Release pre-formed and synthesized molecules to modulate inflammation like histamine and pro-inflammatory prostaglandins and leukotrienes for vasodilation. Activated by C3b/IgE but also temperature and pressure. This is why cold temperatures or pressure from eating food can cause a runny nose.

Involved in Type 1 hypersensitivity (allergic) reactions.

Lymphoid lineage

Will parallel adaptive immune system cells, but lack clonal antigen receptors.

Natural Killer (NK) T-Cells

Activated by IL12 or cells covered in IgG. They will recognize the lack of MHC1 on cells, which are deactivated by virally infected cells to avoid cytotoxic T cells.

They secrete perforin/granzyme which form pores on the infected cells and TRAIL complex which activates caspase 8 in infected cells. Both these result in apoptosis of the target cell.