The chemical messengers of the Immune System

Immunoglubulins(antibodies)

The chemical information of immunoglobulin was provided by Tiselius and Kabat in the early 1940s. In 1950s, Porter and Edelman revealed the basic structure of immunoglobulin molecule. Antibodies are products of antigen- activated B- lymphocytes. They are the main effectors of humoral immunity. They bind antigens with high specificity and affinity.

Structure of Immunoglobulins

This glycoprotein is Y-shaped molecules and has two identical binding sites for its antigen, one on either arm of the Y. This protein is composed of four polypeptide chains (two identical heavy chains and two identical and smaller light chains) held together by disulfide bonds. The antibody molecule has two identical light chains (L chains), each containing about 200 amino acids and two identical heavy chains (H chains), each made up of 400 amino acids. Each chain is made up of several different domains. The antigen-binding site is formed where a heavy chain variable domain (VH) and a light chain variable domain (VL) come close together. These are the domains that differ most in their sequence and structure in different antibodies.

The variable (V) regions

The first 100 or so amino acids at the N-terminal of both H and L chains vary greatly from antibody to antibody. These are the variable (V) regions. The amino acid sequence variability in the V regions is especially pronounced in 3 hypervariable regions. Together they construct the antigen binding site against which the epitope fits. Only a few different amino acid sequences are found in the C-terminals of H and L chains. These are the constant (C) regions.
The constant (C) regions

The two different kinds of C regions for their L chains producing kappa (κ) L chains and lambda (λ) L chains. There are five different kinds of C regions for their H chains producing mu (µ) chains (the H chain of IgM antibodies), gamma (γ) chains (IgG), alpha (α) chains (IgA), delta (δ) chains (IgD) and epsilon (ε) chains (IgE).

Fc and Fab regions

The proteolytic enzyme papain breaks each Ig molecule into 3 fragments at the hinge region. The single crystallizable fragment (Fc region) includes part of the constant domain that occupies the stem. There are 2 antigen-binding fragments (Fab region), which include the entire light chain and variable and constant portions of the heavy chain.

Subclasses of human immunoglobulins

There are nine chemically distinct classes of human immunoglobulins, four kinds of IgG and two kinds of IgA, plus IgM, IgE, and IgD. Immunoglobulins G, D, and E are similar in appearance.

The classes of human immunoglobulins are  based on structure and function.

·         IgM -secreted during primary response

·         IgG -secreted during secondary response

·         IgD -receptors for antigens on B cells

·         IgA -found in external secretions

·         IgF -promotes histamine release

Defense mechanisms of antibodies

 1.Opsonization
2. MAC cytolysis
3. Antibody-dependent cellular cytotoxicity (ADCC) by NK Cells
4. Neutralization of exotoxins
5. Neutralization of viruses
6. Preventing bacterial adherence to host cells
7. Agglutination of microorganisms
8. Immobilization of bacteria and protozoans.

Cytokines

They are non- antibody proteins produced by cells of the immune system (including T cells, B cells, monocytes, and macrophages). Cytokines include a diverse group of interleukins, interferons, and growth factors. Cytokines are chemical switches that turn certain immune cell types on and off. One cytokine, interleukin 2 (IL-2), triggers the immune system to produce T cells. Cytokines also are being studied for their potential clinical benefit.

Kinds of cytokines

1. Monokines - produced by mononuclear phagocytes
2. Lymphokines - produced by activated T cells, primarily helper T cells
3. Interleukins - name given to many cytokines, abbreviated as IL and given a     number

Functions of cytokines

·         Activation of the Immune cells

·         Promotion of cell growth, meaning maturation, and/or division

·         Attraction of cells to the site of infection

·         Destruction infected or malignant cells

·         Stimulation of phagocytic activity.

Chemokines

The name chemokine is a contraction of chemotactic cytokines. These are a large family of substances (more than 50) produced by many different leukocytes and tissue cells. They recruit leukocytes to sites of infection. They play a role in lymphocyte trafficking.
Properties of chemokines
Chemokines are produced by cells involved in both natural and specific immunity. They mediate and regulate immune and inflammatory responses. The secretion is brief and limited. Many individual cytokines are produced by many cell types and act on many cell types (they are pleiotropic). In many cases cytokines have similar actions (they are redundant).

Tumor Necrosis Factor, TNF-gamma

It is produced by activated macrophages. It is the most important mediator of acute inflammation in response to Gram-negative bacteria and other infectious microbes. It mediates the recruitment of polymorphonuclear leukocytes (PMNs) and monocytes to the site of infection: acts on the hypothalamus to produce fever and promotes the production of acute phase proteins by the liver.

Interleukin-2

It is produced mainly by helper T cells (CD4+); less by cytoxic T cells (CD8+). It promotes T cell division and increases production of other cytokines. It has autocrine functions on T cell proliferation.

Interleukin-4

It is produced mainly by Th2 subpopulation of helper T cells (CD4+). It stimulates immunoglobulin class switching to the IgE isotype and development of Th2 cells from naive CD4+ T cells. It also promotes growth of differentiated Th2 cells.

Interleukin-5

It is produced mainly by the Th2 subpopulation of helper T cells (CD4+). It promotes growth and differentiation of eosinophils and activates mature eosinophils.

Interferons (IFN)

There are three groups of interferons: IFN-alpha , IFN-beta , IFN-gamma. Twenty variants of IFN-alpha are produced by leukocytes in response to viruses. IFN-beta is a single protein produced by fibroblasts and other cells in response to viruses. Both IFN-alpha and IFN-beta inhibit viral replication and increase expression of class I MHC on cells. IFN-gamma is produced by the Th1 subpopulation of helper T cells (CD4+), cytotoxic T cells (CD8+), and NK cells. IFN-gamma functions in both natural and specific immunity.

Transforming Growth Factor (TGF-beta)

It is an inhibitory cytokine produced by T cells, macrophages, and many other cell types. It inhibits proliferation and differentiation of T cells. It inhibits activation of macrophages. It acts on PMN and endothelial cells to block the effects of pro-inflammatory cytokines.

The complement system

The complement system consists of more than 35 soluble and cell-bound proteins ,12 of which are directly involved in the complement pathways. The proteins account for 5% of the serum globulin fraction . Most of these proteins circulate as zymogens , which are inactive until proteolytic cleavage . The complement proteins are synthesized mainly by hepatocytes ; however, significant amounts are also produced by Monocytes, macrophages, and epithelial cells in the gastrointestinal and Genitourinary tracts.

Secretory molecules of non-specific immunity

These include organic acids in skin secretions, thiocyanate in saliva, low molecular weight fatty acids in the lower bowel; bile acids and low molecular weight fatty acids in lower GI tract; transferrin, lactoferrin, lysozyme, interferons, fibronectin, complement, acute phase proteins, etc. in serum; Interferons and tumor necrosis factor (TNF) at the site of inflammation. Transferrin and lactoferrin deprive organisms of iron. Interferon inhibits viral replication and activates other cells which kill pathogens. Lysozyme, in serum and tears, breaks down the bacterial cell wall (peptidoglycan). Fibronectin coats (opsonizes) bacteria and promotes their rapid phagocytosis. Complement components and their products cause destruction of microorganism directly or with the help of phagocytic cells. Acute phase proteins (such as CRP) interact with the complement system proteins to combat infections. TNF-alpha suppresses viral replication and activates phagocytes.