immunology allergic disorders
Cellular Components of the Immune System
Lymphocytes
The 2 main types of lymphocytes are B cells (which mature in bone marrow) T cells (which mature in the thymus) The main types of lymphocytes are morphologically indistinguishable but have different immune functions. They can be distinguished by antigen-specific surface receptors and other cell surface molecules called clusters of differentiation (CDs), whose presence or absence define some subsets. More than 300 CDs have been identified many of which are absent from lymphocytes but present on other cells of the immune system. CD molecules function in cell adhesion, cell signaling, as receptors for the Fc region of immunoglobulins, as receptors for components of the complement system, and others. (For further information on CD molecules, see theHuman Cell Differentiation Moleculesweb site.) Each lymphocyte recognizes a specific antigen via surface receptors. About 5 to 15% of lymphocytes in the blood are B cells; they are also present in the bone marrow, spleen, lymph nodes, and mucosa-associated lymphoid tissues. B cells can present antigen to T cells and release cytokines, but their primary function is to develop into plasma cells, which manufacture and secrete Antibodies . Patients with B-cell immunodeficiencies (eg, X-linked Agammaglobulinemia ) are especially susceptible to recurrent bacterial infections. After random rearrangement of the genes that encode immunoglobulin (Ig), B cells collectively have the potential to recognize an almost limitless number of unique antigens. Gene rearrangement occurs in programmed steps in the bone marrow during B-cell development. The process starts with a committed stem cell, continues through pro‒B and pre‒B cell stages, and results in an immature B cell. At this point, any cells that interact with self antigen (autoimmune cells) are removed from the immature B cell population via inactivation (anergy) or apoptosis. Elimination of these cells ensures that the immune system is less likely to recognize these antigens as foreign (immune tolerance). Cells that are not removed (ie, those that recognize nonself antigen) continue to develop into mature naive B cells, leave the marrow, and enter peripheral lymphoid organs, where they may encounter antigens. Their response to antigen has 2 stages: Primary immune response:When mature naive B cells first encounter antigen, they become lymphoblasts, undergo clonal proliferation, and differentiate into memory cells, which can respond to the same antigen in the future, or into mature antibody-secreting plasma cells. After first exposure, there is a latent period of days before antibody is produced. Then, only IgM is produced. After that, with the help of T cells, B cells can further rearrange their Ig genes and switch to production of IgG, IgA, or IgE. Thus, after first exposure, the response is slow and initially provides limited protective immunity. Secondary (anamnestic or booster) immune response:When memory B and Th cells are reexposed to the antigen, the memory B cells rapidly proliferate, differentiate into mature plasma cells, and promptly produce large amounts of antibody (chiefly IgG because of a T cell–induced isotype switch). The antibody is released into the blood and other tissues, where it can react with antigen. Thus, after reexposure, the immune response is faster and more effective. T cells develop from bone marrow stem cells that travel to the thymus, where they go through rigorous selection. There are 3 main types of T cell: Helper Regulatory (suppressor) Cytotoxic In selection, T cells that react to self antigen presented by self MHC molecules (or react strongly to self MHC molecules regardless of the antigen presented) are eliminated by apoptosis, limiting the likelihood of autoimmunity. Only T cells that can recognize nonself antigen complexed to self MHC molecules survive; they leave the thymus for peripheral blood and lymphoid tissues. Most mature T cells express either CD4 or CD8 and have an antigen-binding, Ig-like surface receptor called the T-cell receptor (TCR). There are 2 types of TCR: Alpha-beta TCR: Composed of TCR alpha and beta chains; present on most T cells Gamma-delta TCR: Composed of TCR gamma and delta chains; present on a small population of T cells Genes that encode the TCR, like Ig genes, are rearranged, resulting in defined specificity and affinity for antigen. Most T cells (those with an alpha-beta TCR) recognize antigen-derived peptide displayed in the MHC molecule of an antigen-presenting cell. Gamma-delta T cells recognize protein antigen directly or recognize lipid antigen displayed by an MHC-like molecule called CD1. As for B cells, the number of T-cell specificities is almost limitless. For alpha-beta T cells to be activated, the TCR must engage with antigen-MHC (see figure Two-signal model for T-cell activation ) . Costimulatory accessory molecules must also interact (eg, CD28 on the T cell interacts with CD80 and CD86 on the antigen-presenting cell); otherwise, the T cell becomes anergic or dies by apoptosis. Some accessory molecules (eg, CTLA-4 [cytotoxic T-lymphocyte antigen 4] on the T cell, which also interacts with CD80 and CD86 on the antigen-presenting cell, PD-1 [programmed cell death protein 1] on the T cell, which interacts with PD-L1 [programmed cell death protein ligand 1] on the antigen-presenting cell) inhibit previously activated T cells and thus dampen the immune response. Molecules such as CTLA-4 and PD-1, and their ligands, are termed checkpoint molecules because they signal that the T cell needs to be restrained from continuing its activity. Cancer cells that express checkpoint molecules may thus be protected from the immune system by restraining the activity of tumor-specific T cells. Monoclonal antibodies that target checkpoint molecules on either T cells or on tumor cells (termed checkpoint inhibitors, see table Some Immunotherapeutic Agents in Clinical Use ) are used to prevent downregulation of antitumor immune responses and effectively treat some heretofore resistant cancers and boost the antitumor response. However, because checkpoint molecules are also involved in preventing other types of immune response (such as self-directed autoimmune reactions), checkpoint inhibitors can permit severe immune-related inflammatory and autoimmune reactions to occur (both systemic and organ specific) or exacerbate autoimmune disorders. Polymorphisms in the CTLA-4 gene are associated with certain autoimmune disorders, including Etiology and The alpha (α) and beta (β) chains of the T-cell receptor (TCR) bind to antigen (Ag)–major histocompatibility complex (MHC) on an antigen-presenting cell (APC), and CD4 or CD8 interacts with the MHC. Both actions stimulate the T cell (1st signal) through the accessory CD3 chains. However, without a 2nd (coactivation) signal, the T cell is anergic or tolerant. The TCR is structurally homologous to the B-cell receptor; theαandβ(or gamma [γ] and delta [δ]) chains have constant (C) and variable (V) regions. (1)=1st signal; (2)=2nd signal. Helper T (Th) cellsare usually CD4 but may be CD8. They differentiate from Th0 cells into one of the following: Th1 cells: In general, Th1 cells promote cell-mediated immunity via cytotoxic T cells and macrophages and are thus particularly involved in defense against intracellular pathogens (eg, viruses). They can also promote the production of some antibody classes. Th2 cells: Th2 cells are particularly adept at promoting antibody production by B cells (humoral immunity) and thus are particularly involved in directing responses aimed at extracellular pathogens (eg, bacteria, parasites). Th17 cells: Th17 cells promote tissue inflammation. Each cell type secretes several Cytokines (see table The distinction between the different Th cells is clinically relevant. For example, a Th1 response dominates in tuberculoid Symptoms and Signs , and a Th2 response dominates in lepromatous leprosy. A Th1 response is characteristic of certain autoimmune disorders (eg, type 1 mediate suppression of immune responses and usually express the Foxp3 transcription factor. They comprise functional subsets of CD4 or CD8 T cells that develop either within the thymus (natural Treg) or from conventional T cells upon encounter with antigen in the periphery (induced Treg). Regulatory T cells secrete cytokines such as transforming growth factor (TGF)-beta and interleukin (IL)-10 with immunosuppressive properties, or suppress the immune response by mechanisms that require cell-to-cell contact and involve cell surface molecules such as CTLA-4 and CD25. Patients with functional mutations in Foxp3 develop the autoimmune disorder IPEX Syndrome ( Cytotoxic T (Tc) cellsare usually CD8 but may be CD4; they are vital for eliminating intracellular pathogens, especially viruses. Tc cells play a role in organ transplant rejection. Tc-cell development involves 3 phases: A precursor cell that, when appropriately stimulated, can differentiate into a Tc cell An effector cell that has differentiated and can kill its appropriate target A memory cell that is quiescent (no longer stimulated) but is ready to become an effector when restimulated by the original antigen-MHC combination Fully activated Tc cells, like natural killer (NK) cells, can kill an infected target cell by inducing apoptosis. Tc cells can secrete cytokines and, like Th cells, have been divided into types Tc1 and Tc2 based on their patterns of cytokine production. Tc cells may be Syngeneic: Generated in response to self (autologous) cells modified by viral infection or other foreign proteins Allogeneic: Generated in response to cells that express foreign MHC products (eg, in organ transplantation when the donor’s MHC molecules differ from the recipient’s) Some Tc cells can directly recognize foreign MHC (direct pathway); others may recognize fragments of foreign MHC presented by self MHC molecules of the transplant recipient (indirect pathway). are a distinct subset of T cells. Activated NKT cells secrete IL-4 and interferon-gamma and may help regulate immune responses. NKT cells differ from Natural Killer (NK) Cells in phenotype and certain functions. 