Ch. 7 Complements

Didn't add pathways!!!!!!!!!!!!!!!!!!!!!!!!!!!

Complement

series of 50+ soluble and cell-bound proteins that interact to enhance host defense mechanisms against foreign cells

Most plasma complement proteins are synthesized in the

liver (except C1 + Factor D)

Monocytes/macrophages are additional sources of complements…

C1, C2, C3, C4

Most complements are

zymogens (inactive precursor) that are converted to active enzymes

Complement synthesis increases in

acute inflammation

Complements are decreased in

chronic inflammation or liver disease

Functions of Complement Components

• host defense against infection (cause of lysis)

• Inflammation (opsonization, increase vascular permeability)

• Clears immune complexes

Complements are the link between innate and acquired immunity because

• C3b, C4b etc have roles in activation B cells + antigen presenting cells

• Trigger secretion of immunoregulatory molecules that amplify the immune response

• Enhancing memory through interactions with B cells and follicular dendritic cells

Complement activation

C proteins alteration such that they interact with next component

Complement fixation

utilization of complement by ag-ab complexes

Complement inactivation

early C component denaturation resulting in cell lytic activity loss

Convertase/esterase

altered C proteins which acts as proteolytic enzyme for another C component

Stages of the Classical Pathway

C1 - C9

1. Reconition: C binds to antigen-antibody complex

2. Activation: Ca fragments are created & combine to form active enzymes

3. Membrane attack: attaching complex is formed → cell lysis

Substances that initiate the Classical Pathway

• Antibodies (IgG + IgM mainly)

• C-reactive protein

• mycoplasmas

• gram (-) bacteria

Complement Activation

piece that “floats away” & has biological activities in solution “a” component

• execption: C2 → Cb component floats away

The Lectin Pathway is activated by

carbohydrates on microbial cell walls

Lectin Pathway involves 3 classes of recognition molecules

lectins, ficolins, CL-L1

Mannan-binding lectin (MBL)

• acute-phase protein

• Binds to mannose or related sugars on microbes to initiate pathway

Alternative pathway acts mainly as an…

amplification loop for classical or lectin pathways

Alt. Pathway involves

C3, C5-C9, Factors B,D, and P

Alt. Pathway can be activated by

• LPS

• fungal/yeast/virus

• virally infected cells

• Tumor cells

• some parasites

Complement System regulators

• plasma proteins (doesn’t harm self/localized rxns)

• Certain cell receptors

• C3 step to halt accumulation of C3b

C1 inhibitor (C1INH) inactives C1 and its removal causes….

C1r and C1s to dissociate from C1q

CR1 (complement receptor type 1) (CD35) Classical Pathway Regulator

• on peripheral blood cell surface

• binds to C3b, C4b, then degraded by factor 1

• CR1 on RBC bind to C3b coated immune complex & brings it to liver/spleen

Immune adherence

the ability of cells to bind complement-coated particles

DAF (Decay accelerating factor) CD55 Classical Pathway Regulator

• Dissociation of C2 → Bb binding (halts formation of classical/alt. C3 convertases)

• Used for indenfitication of self vs. non self

Factor H Alt. Pathway Regulator

• binds to C3b which binds to Factor I

• Factor I breaks down C3b to C3dg

C1INH also inhibits the lectin pathway by

inhibiting binding of MBL-MASP-2

S Protein

• prevents attachment of C5b67 complex to cell membrane

• Prevents bystander cell damage by membrane active components

CD59

blocks C9 insertion (on all blood, endothelial, and epithelial cells)

Complement fragment (a)

• amplifies inflammatory response

• facilitates B-cell activation

Anaphylatoxins

C5a, C4a, C2a

Chemotaxins

C5a

Opsonins

C3b, C4b, iC3b, C3dg, C1q

C3 deficiency affects all pathways, leading to

• decrease phagocytosis, immune complex clearance, class switching

• seseptible to recurrent bacterial infections

C5-C9 terminal compoent deficiency leads to

• SLE (lupus)

• unable to penetrate outer membrane of G(-) bacteria

C1, C4, and C2 deficiencies increase risk of

• autoimmune connective tissue diseases

• recurrent infections

Lectin pathway deficiencies

associated with bacterial infections with infants

Alt. pathway deficiencies

• pyogenic bacteria

• not able to opsonize bacteria

• affects properdin, factors H, I, B, or D, MASP-2

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• deficiencies of DAF and CD59

• chronic hemolytic anemia

Hereditary angioedema (HAE)

• C1 inhibitor deficiency

• Increase in C1s activities

• Swelling

Atypical hemolytic uremic syndrome (aHUS)

• kacute renal failure in children

• mutations in factor H, I, B. MCP, C3, thrombomodulin, or autoantibodies against factor H

C3 glomerulopathy

inflammation of the renal glomeruli that may be due to autoantibodies that cause C dysregulation

Antigenic assays

measure amount of each component (protein) in serum but does not distinguish if functionally active

Functional assays

measure functinoal activity of components or pathways

CH50 Assay

dilution that 50% antigen coated cells lysed

AH50

measure function initiated through alternative pathway

measurement of complement activation products (C5a/C5b-9)

CH50 and AH50 require complement components

C3 and C5-9

CH50 needs

C1, C2, C4, C1INH

AH50 needs

Factor B, Factor D, Properdin and Factor H + I

High complement levels indicate

acute inflammation

Low complement levels indicate

• genetic deficiencies

• Chronic infection

• incorrectly processed serum samples