bio 151 lec 11 complement

BIOLOGY 151 LECTURE 11

The Complement

PARUNGAO-BALOLONG 2011Sunday, March 13, 2011

PARUNGAO-BALOLONG 2011

WHAT YOU NEED TO KNOW

RECALL: Functions & Components of the Complement

Activation and Regulation of the Complement Cascade

Biological Consequences

Sunday, March 13, 2011

PARUNGAO-BALOLONG 2011RECALL...Sunday, March 13, 2011

Complement...Paul Erlich (1890s)

describe how cells respond to a range of different threats

proposed that cells produce more of these side chains, which eventually break off, circulate in the blood stream and attach to toxic products released by bacteria (ANTIBODIES)

Jules Bordet (1900s)

experiments revealed how antibodies need to recruit special allies in order to destroy specific bacteria

wasn’t sealed by antibodies alone (partner up with a substance that is routinely present in the blood = COMPLEMENT) PARUNGAO-BALOLONG 2011


PATHWAYS OF ACTIVATION


THE COMPLEMENT CASCADE


FUNCTIONS AND COMPONENTS OF THE COMPLEMENT

trigger inflammation

attract phagocytes

opsonize antigens

cause cell lysis

activate naïve B-lymphocytes

remove immune complexes

Synthesized mainly by liver hepatocytes (blood monocytes, tissue macrophages, epithelial cells of GI &GU tracts)

Most circulate in the serum in functionally inactive forms as proenzymes (zymogens)

ACTIVATION:

larger fragments: bind to the target near the site of activation

smaller fragments: local inflammation PARUNGAO-BALOLONG 2011


STRUCTURE OF C1q

http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/c1act.html

assembly of C1 during classical pathway








SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION



CLASSICAL PATHWAY


assembly of C1 during classical pathway

http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/c3case.html

assembly of C3 convertase


cleavage of C3 and assembly of C5 convertaseSunday, March 13, 2011













C3 MOLECULES & THIOESTER BONDS


HYDROLYSIS OF C3 BY C3 CONVERTASE C4b2a


ALTERNATIVE PATHWAY (PROPERDIN PATHWAY)

a primitive defense system, a bypass mechanism that does not require C1, C4, and C2 interaction (does not depend on antibody for its activation)

Activation

immunologically (e.g., by IgA and some IgG)

non immunologically (e.g., by certain microbial cell surfaces, complex polysaccharides, and bacterial lipopolysaccharides)



COMPONENTS: ALTERNATIVE PATHWAY (PROPERDIN PATHWAY)

C3: The initial recognition event necessary for alternative pathway activation is the presence of C3, specifically C3b, which is probably continuously generated in small amounts in the circulation

Factor B (C3 proactivator)

C3b interacts with factor B, to form C3bB, which is a magnesium ion-dependent complex




Factor D (C3 proactivator convertase)

The complex C3bB is susceptible to enzymatic cleavage by factor D, into two fragments, Ba and Bb (Ba fragment is released)

An active site is exposed in the Bb fragment, which remains bound to C3b, forming the C3bBb (amplification C3 convertase)




Factor D

When stabilized by the binding of properdin (P), which slows the dissociation of Bb, the C3bBb complex becomes a C3 convertase that cleaves C3 and generates more C3b

C3b then fixes to the activator surface so that more factor B binding sites are exposed

As more C3b is generated, the complex expands and becomes a C5 convertase (cleaving C5 into C5a and C5b and initiating the membrane attack pathway) PARUNGAO-BALOLONG 2011


The mannose-binding lectin pathway

does not depend on antibody for its activation; originates with host proteins (MBL) binding microbial surfaces

MBL, an acute phase protein, binds to mannose residues, and to certain other sugars on many pathogens

MBL, like C1q, is a two- to six-headed molecule that forms a complex with two protease zymogens (MASP-1 and MASP-2)



The mannose-binding lectin pathway

When the MBL complex binds to a pathogen surface, MASP-2 is activated to cleave C4 and C2

A C3 convertase is formed from C2a bound to C4b

The MBL pathway is of importance in innate host defense mechanisms in early childhood



The three complement pathways converge at the membrane-attack complex



Late steps of complement activation and formation of the MAC (membrane attack complex)



EFFECTOR ACTIONS OF COMPLEMENT



Antibody-mediated mechanisms for combating infections by extracellular bacteria



Scanning electron micrographs of E. coli showing (a) intact cells and (b, c) cells killed by complement-mediated lysis



MICROBIAL EVASION



formation of larger viral aggregates - reduce the net number of infectious viral particles

a coating of Ab and/or complement to the surface of a viral particle

blocking attachment to susceptible host cells - facilitate binding of the viral particle to cells

possessing Fc or CR1 - lysing most enveloped viruses

The complement system neutralizes viral infectivity Electron micrographs of negatively stained preparations of EB virus



REGULATIONInclusion of highly labile components that undergo spontaneous inactivation if they are not stabilized by reaction with other components

A series of regulatory proteins (regulators of complement activation [RCA] gene cluster - chromosome 1 in humans)



REGULATION: RECEPTORSMany of the biological activities of the complement system depend on the binding of complement fragments to complement receptors, which are expressed by various cells



ROLE OF COMPLEMENT IN B CELL ACTIVATION



COMPLEMENT & DISEASESComplement deficiencies

genetic deficiencies in classical pathway components (C1q, C1r, C4, C2 and C3)

deficiencies in components of the alternative pathway (properdin, factor D, C3)

deficiencies in the terminal complement components (C5, C6, C7, C8, C9, Neisseria bacteria)

deficiencies in complement regulatory proteins (abnormal complement activation)

deficiencies in complement receptors (CR3 & CR4 – inadequate adherence of neutrophils to endothelium at tissue sites of infection)



COMPLEMENT & DISEASES

Pathologic effects of a normal complement system

The immune complexes produced in autoimmune diseases may bind to vascular endothelium and kidney glomeruli and activate complement (MAC generation)

It initiates the acute inflammatory responses that destroy the vessel walls or glomeruli and lead to thrombosis, ischemic damage to tissues, and scarring

Some of the late complement proteins may activate prothrombinases in the circulation that initiate thrombosis



What is the rate-limiting step in the complement cascade?

C4. The liver can produce a finite amount of C4

In rare cases, when an angioedema attack is treated with large amounts of FFP, symptoms may worsen because of a temporary C4 depletion


WRAPPING UP!!!

The complement system comprises a group of serum proteins, many of which exist in inactive forms

Complement activation occurs by the classical, alternative, or lectin pathways, each of which is initiated differently

The three pathways converge in a common sequence of events that leads to generation of a molecular complex that causes cell lysis



WRAPPING UP!!!

The classical pathway is initiated by antibody binding to a cell target; reactions of IgM and certain IgG subclasses activate this pathway

Activation of the alternative and lectin pathways is antibody- independent. These pathways are initiated by reaction of complement proteins with surface molecules of microorganisms

In addition to its key role in cell lysis, the complement system mediates opsonization of bacteria, activation of inflammation, and clearance of immune complexes



WRAPPING UP!!!

Interactions of complement proteins and protein fragments with receptors on cells of the immune system control both innate and acquired immune responses

Because of its ability to damage the host organism, the complement system requires complex passive and active regulatory mechanisms

Clinical consequences of inherited complement deficiencies range from increases in susceptibility to infection to tissue damage caused by immune complexes



NEXT MEETING: CELL-MEDIATED

EFFECTOR RESPONSE


bio 151 lec 11 complement

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