Immunology basics

Immunoglobulins

B-lymphocytes when fully differentiated turn into plasma cells which produces antibodies.

Antibodies are present in plasma proteins. 

Plasma proteins are negatively charged at body pH.

Globulins are heavy molecular weight molecules of plasma protein which move towards the negative pole in electrophoresis

Albumins are lightest molecular weight molecules (70 KD) of plasma protein which move towards the positive poles in electrophoresis.

Plasma proteins are in globulins.  They are part of gammaglobulins

Antibodies = immunoglobulin = gamma globulin

Antibodies are protein molecules which react readily and specifically to antigens that stimulated their synthesis.

Antibodies are glycoproteins.  They have a tetrapeptide structure.  2 heavy chains and 2 light chains, both held together by disulfide bonds.

Hypervariable regions are present within the variable regions and impart more specific ab-ag and precision. 

Forces that bind: electrostatic and Vanderwaal forces.

Complement system

Complement is a group of 30 or more plasma and cell surface proteins, mainly synthesized in the liver and distributed in the blood and tissues.  Many complements are also elaborated by macrophages.  C1 is mainly produced by GI mucosa.

Complements are proenzymes and are circulated in inactive state.  They get activated only in case of immune activity.  

They work in concert to fight the invading microorganisms through phagocytosis, inflammation, and lysis.

• Opsonization: Complement acts like a glue to attach antigens or antigen antibody complexes to macrophages or neutrophils for easier phagocytosis.

• Inflammation: Complement induces histamine release by mast cells and basophils, dilating blood vessels, and making them more leaky to inflammatory cells and proteins.

• Lysis: Complement induces bacterial lysis.

The sequence of events in the complement pathways is as follows:  

1. Activation.  

2. Formation of the enzyme C3 convertase.  

3. Opsonization and phagocytosis.  

4. Inflammation.  

5. Lysis.  

1.  Activation.  The activation of complement occurs via 3 distinct pathways: Classical, alternative, and lectin.

Classical pathway:  The components of the classical pathway include C1 (C1q, C1r, and C1s), C2, C3, and C4.  The activation of this pathway is initiated by binding of C1, the first component of the complement system, to the antigen antibody complex.  

• Antigens are substances (usually external) that enter the body, bind antibody or T-cell receptor, and elicit an immune response.  

• Antibody (also known as immunoglobulin) glycoprotein produced by plasma cells in response to antigen.

Alternative pathway: The components of the alternative pathway include properdin, factor B, factor D, and C3.  The activation of this pathway is initiated directly on microbial cell surfaces and is independent of antibodies.

Lectin pathway: The activation of lectin pathway starts when a protein known as mannose-binding lectin (MBL) recognizes mannose residues on the microbial surface.  After activation of the mannose-binding lectin-associated proteases, MASP-1 and MASP-2 , the remaining part of the pathway is similar to the classical pathway.

2.  Formation of the enzymes C3 convertase.  After several steps of binding and enzymatic events, the enzyme C3 convertase is formed (C3bBb amd C4b2a).  This enzyme cleaves C3, the most abundant component of the complement system and the center of all complement action, into 2 components: C3a and C3b.

3.  Optimization and phagocytosis.  Opsonization is the binding or coating of a microbe by an antibody or a complement.  Such binding tags the microbe as a target and identifies it as an easy mark for phagocytosis.  The molecule that binds to the microbe, in this case complement, is an opsonin.  C3b is an example.  Phagocytes that have receptors on the cell surfaces bind to the the opsonized molecules and engulf them.

4.  Inflammation.  C3a and C5a are able to attract neutrophils (chemoattraction).  They also have anaphylotoxic activity, in which they bind to and stimulate mast cells and basophils to release the contents of the cytoplasmic granules (degranulation), including histamine and other vasoactive substances.  Binding of histamine to the endothelial layer of capillaries causes their dilation, which allows leakage of fluid and proteins from the blood to the adjacent tissues, leading to inflammation.

5.  Lysis.  C3b. cleaves C5 to form C5a and C5b.  On the surface of the microbe, C5b forms a complex with C6, C7, C8, and C9 known as membrane attack complex (MAC) and causes the lysis of the microbe.

When a bacterial antigen activates the humoral response IgM, IgG are the only immunoglobulins that activate complement system.  A single molecule of IgM or a double molecule of IgG activate complement. 

Macrophage takes up the antigen and presents to Th (helper) cells > B cells >>turn into>> plasma cells.  Plasma cells secretes antibodies.  When ab react with ag there is a change in the tail of ab.  The Fc portion of ab has a special loop that becomes available when ab binds to ag.  When ab-binds to ag, it undergos a transformational change and exposes special domains in the loop that bind and activate the complementary cascade.  In normal state these domains are not exposed and so they do not bind and activate the complement. 

IgG or IgM >> bound at Fc portion by C1q > C1 + (C4bC2b = a.k.a C3 convertase) + C3b (a.k.a C5 convertase) >>late events>>C5b+C6+C7+C8+C9

C1 = C1q, C1r, C1s (3 peptides of C1)

C1 does not fragment in C1b and C1a after binding to the Fc portion of Ig.

C3 is the central complement.

C4bC2b is C3 convertase > C3b

C4bC2bC3b is C5 covertase > C5b.

IgG, IgG2, IgG3 can activate complement cascade.

IgG4 cannot activate complement.

C5b binds to C6, C7, then to C7, C8, C9.  All of them combined are called MAC (membrane attack complex) which causes a pentameric hole in the bacterial membrane.

Early events in activation of complement: C4b, C2b, C3b.

Terminal events (late) in activation of complement: C5b, C7, C8, C9.

MAC is more effective on gram negative bacteria as they have a thin peptoglycan layer and lipid membrane. It is less effective on gram positive bacteria. 

Hypocomplementemia makes a person susceptible to gram negative bacteria like Nesseria gonococci and meningococci.  These are more prevalent in patients with terminal hypocomplement deficiency.