Table of Contents
- Activation of B cells requires two signals. Depending on the kind of antigen, B-cell activation occurs via two different pathways, one dependent on helper T cells (TH cells) and the other not.
- The connection between CD40 of B cells and CD40 ligand of T cells gives a second signal for T-dependent antigen, whereas cross-linking of membrane-bound immunoglobulin to polymeric carbohydrate provides the signal for T-independent antigen.
- The B-cell response to thymus-dependent (TD) antigens requires direct contact with TH cells, as opposed to mere exposure to TH-produced cytokines.
- Antigens that can activate B cells in the absence of this form of direct interaction by TH cells called thymus-independent (TI).
- Types 1 and 2 of TI antigens activate B cells in different ways, while polymeric proteins such as bacterial flagellin function as Type 2 thymus-independent (TI-2) antigens.
Thymus-Independent Antigens (T Independent Antigen)
- Without the support of CD4 T cell helper cells, certain antigens can directly activate B cells and induce a humoral antibody response.
- Common examples of T-independent antigens include lipopolysaccharides, polymerized flagellin, and pneumococcal polysaccharides, as well as their close homologues, dextrans, polyvinylpyrrolidone, and Ficoll.
- These antigens either cross-link several B-cell receptors, activating the B cell, or bind to the B-cell receptor and other receptors on B cells (TI-1 antigens like lipopolysaccharides of Gram-negative bacteria) (TI-2 antigens such as pneumococcal polysaccharide or polymerized flagellin).
- Most of these T-independent antigens have the ability to act as polyclonal B-cell activators, which are B-cells’ non-specific mitogens.
- T-independent antigens elicit a quicker humoral immune response because they do not require antigen processing and presentation by CD4 T cell helper cells.
- However, the T-independent response is constrained because only IgM is produced, and there is no opportunity to improve antibody affinity through this route.
- A specialised immune response, which typically involves helper CD4 T cells, takes time to develop, therefore it is thought that this reaction originated and persisted to allow for a rapid humoral response to the first bacterial invasion.
- In spite of its potential benefits for immunological defence, the humoral immune response to T-independent antigens plays no major role in the experimental production of polyclonal antibodies.
Properties of Thymus-Independent Antigens (T Independent Antigen)
- A thymus-independent antigen is an immunogen that can trigger B cells to produce antibodies in the absence of T cells.
- The complexity of these antigens is smaller than that of thymus-dependent antigens.
- They are often polysaccharides with repeated epitopes or lipopolysaccharides originating from Gram-negative bacteria.
- Thymus Independent antigens promote IgM production by B cells without T cell participation.
- Additionally, they do not promote immunological memory.
- Antigens that are independent of the thymus in mice are classed as either TI-1 or TI-2 antigens.
- A typical TI-1 antigen is lipopolysaccharide (LPS), which activates murine B cells without the assistance of T or other cells.
- Low quantities of LPS stimulate the manufacture of particular antigen, but large concentrations stimulate the growth and differentiation of almost all B cells.
- TI-2 antigens contain polysaccharides, glycolipids, and nucleic acids. When T cells and macrophages are eliminated, there is no antibody reaction against them.
Thymus-Dependent Antigens (T Dependent Antigen)
- In the secondary lymphoid tissues, specific antigen, B-cells, professional antigen-presenting cells, and CD4 T cells interact to produce antibodies to thymus-dependent antigens.
- Antigen is either carried to lymphoid tissues by dendritic cells, lymphatics, or by direct contact, where it is phagocytosed by macrophages.
- Antigen is processed by antigen-presenting cells and presented to antigen-specific CD4 T-cells together with MHC class II molecules in both instances. This connection activates antigen-specific T-cell helper cells.
- As B-cells move through the T-cell regions of secondary lymphoid tissue, those that recognise their specific antigen are bound and then activated via specific contacts with antigen-specific helper T-cells.
- In the T-cell region of lymphoid tissue, this results in the creation of a primary concentration of rapidly proliferating B lymphoblasts. Some of the rapidly proliferating B lymphoblasts migrate to the medullary cords and mature into plasma cells that produce antibodies.
- Other B lymphoblasts migrate to the primary follicles, where they join to their respective T-cell helper cells to form the germinal centre.
- These B lymphoblasts, which are now known as centroblasts, are huge, metabolically active cells with a high mitotic rate. The centrocyte, a collection of B-cells expressing a changed surface immunoglobulin with a spectrum of affinities to the antigen, is the result of the centroblasts’ fast division and somatic hypermutation.
- The centrocyte competes with other centrocytes for antigen access and antigen-specific helper T-cells, hence selecting for antigen-affine cells.
- This antibody maturation selects centrocytes with the highest antigen affinity for further differentiation into antibody-producing plasma cells and long-lived memory B cells.
- Utilizing a rabbit to manufacture antibody against a single immunogen has been the conventional method for producing polyclonal antibodies.
- The rabbit is able to mount an antibody response to numerous immunogens simultaneously, resulting in an antigen-reactive final product.
- In certain circumstances, immunising a rabbit with numerous immunogens affords the chance to conserve resources and increase productivity.
- To isolate monospecific antibodies, care must be taken to ensure that the antibodies generated to the respective immunogens do not interfere with the intended usage of each antibody, or affinity purification procedures can be used.
- Antibody-based proteomics is an example of a sector where the immunisation of rabbits with various immunogens followed by affinity purification to get monospecific antibodies is well known.
Properties of Thymus-Dependent Antigens (T Dependent Antigen)
- Antigens dependent on the thymus include different epitope-containing proteins, polypeptides, hapten carrier complexes, erythrocytes, and several other antigens.
- T dependent antigens contain some epitopes recognised by T cells and others by B cells.
- T cells generate cytokines and cell surface chemicals that stimulate B cell proliferation and differentiation into antibody-producing cells.
- Immune responses to T-dependent antigens involve isotype switching, development of affinity, and memory.
- The response to thymus-dependent antigens exhibits minimal heavy chain isotype switching or affinity maturation, both of which are dependent on helper T cell signals.
Main steps during B-cell activation by a thymus-dependent antigen
- Internalized, processed, and presented as peptide-MHC-II complexes are soluble protein antigens which attach to membrane-bound immunoglobulin on the surface of B cells.
- TH cell detects class II MHC-antigen complex on B-cell surface via TCR. Via CD28, it also interacts with the costimulatory molecule B7. These interactions stimulate TH cell activity. TH cells that are activated generate several cytokines.
- TH cells start to produce CD40L and interact with B cell CD40. The link between CD40 and CD40L generates a second activation signal for B cells.
- B cells start to express cytokine receptors and bind to cytokines produced by TH cells. That which activates B cells and causes them to develop into plasma cells.
- The activated B-cell proliferates clonally to produce plasma cells and memory cells that all detect the same antigen.
This CD40/CD40L interaction is crucial for B-cell survival, development of germinal centres, production of memory-cell populations, and somatic hypermutation (for affinity maturation).
Difference between T dependent Antigen and T independent Antigen
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