Antigen & Cellular basis of Immunity

Aman Ullah

ANTIGENS• Antigens are molecules that react with antibodies• immunogens are molecules that induce an immune response• In most cases, antigens are immunogens• However, there are certain important exceptions, e.g., haptens• Haptens are not immunogenic because they cannot activate

helper T cells• The failure of haptens to activate is due to their inability to

bind to MHC proteins; because they are not polypeptides and only polypeptides can be presented by MHC proteins

• Haptens are also univalent and therefore cannot activate B cells by themselves

Factor affecting immunogenicity1. Foreignness: To be immunogenic, molecules must be recognized

as "nonself," i.e., foreign2. Molecular size: Molecule with different size have different

immunogenicity3. Chemical-structural complexity: A certain amount of chemical

complexity is required4. Antigenic determinants (epitopes): Epitopes are small chemical

groups on the antigen molecule that can elicit and react with antibody. An antigen can have one or more determinants (epitopes). Most antigens have many determinants; i.e., they are multivalent

5. Dosage, route, and timing of antigen administration6. Adjuvants: Enhance the immune response to an immunogen

Cellular Basis of the Immune Response

Origin of immune cells• The capability of responding to immunologic stimuli

rests mainly with lymphoid cells• During embryonic development, blood cell precursors

originate mainly in the fetal liver and yolk sac; in postnatal life, the stem cells reside in the bone marrow

• Stem cells differentiate into cells of the erythroid, myeloid, or lymphoid series

• Lymphoid series evolve into two main lymphocyte populations: T cells and B cells

Origin of T and B cells• Stem cells in the bone marrow (or fetal liver) are the

precursors of both T and B lymphocytes• Stem cells differentiate into T cells in the thymus, whereas

they differentiate into B cells in the bone marrow• Within the thymus, T cells become either CD4-• positive (helper) cells or CD8-positive (cytotoxic) cells• B cells can differentiate into plasma cells that produce

large amounts of antibodies (immunoglobulins)• T-cell precursors differentiate into immunocompetent T

cells within the thymus

Origin of T and B cells

• Stem cells lack antigen receptors and lack CD3, CD4, and CD8 proteins on their surface

• During passage through the thymus they differentiate into T cells that can express both antigen receptors and the various CD proteins

• The stem cells, which initially express neither CD4 nor CD8 (double-negatives), first differentiate to express both CD4 and CD8 (double-positives) and then proceed to express either CD4 or CD8

Thymus education1. CD4-positive, CD8-positive cells bearing antigen receptors for

"self" proteins are killed (clonal deletion) by a process of "programmed cell death" called Apoptosis. The removal of these self-reactive cells, a process called negative selection, results in tolerance to our own proteins, i.e., self-tolerance, and prevents autoimmune reactions

2. CD4-positive, CD8-positive cells bearing antigen receptors that do not react with self MHC protein are also killed. This results in a positive selection for T cells that react well with self MHC proteins

• During their passage through the thymus, each double-positive T cell synthesizes a different, highly specific antigen receptor called the T-cell receptor (TCR)

Origin of T and B cells

• B-cell precursors differentiate into immunocompetent B cells in the bone marrow

• B cells also undergo clonal deletion of those cells bearing antigen receptors for self proteins, a process that induces tolerance and reduces the occurrence of autoimmune diseases

• The site of clonal deletion of B cells is uncertain

Natural Killer cell• Natural killer (NK) cells are large granular lymphocytes that do

not pass through the thymus, do not have an antigen receptor, and do not bear CD4 or CD8 proteins

• They recognize and kill target cells, such as virus-infected cells and tumor cells, without the requirement that the antigens be presented in association with class I or class II MHC proteins

• NK cells target those cells to be killed by detecting that they do not display class I MHC proteins on the cell surface

• This detection process is effective because many cells lose their ability to synthesize class I MHC proteins after they have been infected by a virus

Natural Killer cell• NK cells play an important role in the innate host defenses• They are called "natural" killer cells because they are active

without prior exposure to the virus, are not enhanced by exposure, and are not specific for any virus

• They can kill without antibody, but antibody (IgG) enhances their effectiveness, a process called antibody-dependent cellular cytotoxicity (ADCC)

• IL-12 and gamma interferon are potent activators of NK cells• Approximately 5–10% of peripheral lymphocytes are NK cells• NK cells detect the presence of cancer cells by recognizing a

protein called MICA that is found on the surface of many cancer cells but not normal cells

• Interaction of MICA with a receptor on NK cells triggers the production of cytotoxins by the NK cell and death of the tumor cell

Polymorphonuclear neutrophils• Neutrophils are a very important component of our innate

host defenses, and severe bacterial infections occur if they are too few in number (neutropenia) or are deficient in function

• They have cytoplasmic granules• These granules are lysosomes, which contain a variety of

degradative enzymes that are important in the bactericidal action of these cells

• The perform phagocytosis • Neutrophils have receptors for IgG on their surface so IgG is

the only immunoglobulin that opsonizes, i.e., makes bacteria more easily phagocytosed

Eosinophil• Eosinophils are white blood cells with cytoplasmic granules• The function of eosinophils has not been clearly established• It seems likely that their main function is to defend against the migratory larvae

of nematodes, such as Strongyloide• They attach to the surface of the larvae and discharge• the contents of their granules, which in turn damages the cuticle of the larvae• Attachment to the larvae is mediated by receptors on the eosinophil surface for

the Fc portion of the heavy chain of IgG and IgE• Another function of eosinophils may be to mitigate the effects of immediate

hypersensitivity reactions because the granules of eosinophils contain histaminase, an enzyme that degrades histamine, which is an important mediator of immediate reactions

• Eosinophils can phagocytose bacteria but they do so weakly and are not sufficient to protect against pyogenic bacterial infections in neutropenic patients

Basophils & Mast cells• Basophils are white blood cells with cytoplasmic granules and circulate in the

bloodstream• Whereas mast cells, which are similar to basophils in many ways, are fixed in tissue,

especially under the skin and in the mucosa of the respiratory and gastrointestinal tracts

• Basophils and mast cells have receptors on their surface for the Fc portion of the heavy chain of IgE

• When adjacent IgE molecules are cross-linked by antigen, immunologically active mediators, such as histamine, and enzymes, such as peroxidases and hydrolases, are released

• These cause inflammation and, when produced in large amounts, cause severe immediate hypersensitivity reactions such as systemic anaphylaxis

• Mast cells also play an important role in the innate response to bacteria and viruses• The surface of mast cells contain Toll-like receptors that recognize bacteria and

viruses and respond by releasing cytokines and enzymes from their granules that mediate inflammation and attract neutrophils and dendritic cells to the site of infection

Antigen-presenting cells

Macrophages: • Have three main

functions: 1. Phagocytosis 2. Antigen

presentation 3. Cytokine

production

Macrophages• These three functions are greatly enhanced when a process called

macrophage activation occurs• Macrophages are activated initially by substances such as bacterial

lipopolysaccharide (LPS, endotoxin), by bacterial peptidoglycan, and by bacterial DNA (Human DNA is methylated, whereas bacterial DNA is unmethylated and therefore is perceived as foreign.) These substances interact with "toll-like receptors" on the macrophage surface and signal the cell to produce certain cytokines

• Macrophages are also activated by gamma interferon produced by helper T cells

• Gamma interferon increases the synthesis of class II MHC proteins, which enhances antigen presentation and increases the microbicidal activity of macrophages

Macrophages

• Macrophages are derived from bone marrow histiocytes

• Exist both free, e.g., monocytes, and fixed in tissues, e.g., Kupffer cells of the liver

• Macrophages migrate to the site of inflammation, attracted by certain mediators, especially C5a, an anaphylatoxin released in the complement cascade

Dendritic Cells• Dendritic cells are a third type of cell that function as "professional"

antigen presenting cells (macrophages and B cells are the other two)• They express class II MHC proteins and present antigen to CD4-

positive T cells• They are particularly important because they are the main inducers

of the primary antibody response• The name "dendritic" describes their many long, narrow processes

(that resemble neuronal dendrites), which make them very efficient at making contact with foreign material

• Dendritic cells are primarily located under the skin and the mucosa, e.g., Langerhans' cells in the skin

• Dendritic cells migrate from their peripheral location under the skin and mucosa to local lymph nodes, where they present antigen to helper T cells