Neuroimmunology

Monocytes and Macrophages

Bone marrow–derived myeloid progenitor cells give rise to monocytes (mononuclear phagocytes of the reticuloendothelial system) that serve important immune functions. They constitute about 4% of the peripheral blood leukocytes and are morphologically identified by an abundant cytoplasm and a kidney-shaped nucleus. Their cytoplasm contains many enzymes, which are important for killing microorganisms and processing antigens. Monocytes differentiate into tissue-specific macrophages including Kupffer cells of the liver and brain microglia.

Natural Killer Cells

NK cells make up about 2.5% of peripheral blood lymphocytes and are synonymous with large granular lymphocytes because of their large intracytoplasmic azurophilic granules and high cytoplasm-to-nucleus ratio. NK cells are activated primarily in response to interferons and are involved in the elimination of virally infected host cells; they also play a role in tumor immunity. Unlike cytotoxic CD8 ⁺ T cells, NK cells lack immunological memory and have the ability to kill a wide variety of tumor and virus-infected cells without MHC restriction (see the discussion of the function of MHC genes) or activation. NK cells lack the cell surface markers present on B cells and T cells. NK1.1 ⁺ T cells are a subset of cells sharing characteristics of both NK cells and T cells. These cells express the α/β TCR and the NK1.1 receptor and secrete large amounts of interferon gamma (IFN-γ) or interleukin 4 (IL-4) in response to TCR stimulation.

T Lymphocytes

T cells originate from the thymus. Differentiation of T cells occurs in the thymus, and every T cell that leaves the thymus is conferred with a unique specificity for recognizing antigens. T cells that recognize self-antigens are generally either deleted or rendered tolerant within the thymus, a process called central tolerance .

T cells may be divided into two groups on the basis of expression of either the CD4 ⁺ or CD8 ⁺ marker. Functionally, CD4 ⁺ T cells are involved in DTH responses and also provide help for B-cell differentiation (and hence are termed helper T cells ). In contrast, CD8 ⁺ T cells are involved in class I restricted lysis of antigen-specific targets (and hence are termed cytotoxic T cells ). T cells with suppressor or regulatory activity can express either CD4 or CD8.

T-Cell Receptors

The TCR consists of two glycosylated polypeptide chains, alpha (α) and beta (β), of 45,000 and 40,000 Da molecular weight, respectively. This heterodimer of an α and β chain is linked by disulfide bonds. Amino acid sequences show that each chain consists of variable (V), joining (J), and constant (C) regions closely resembling Igs ( Fig. 49.1 ). There are about 10 ² TCR-variable genes grouped by homology into a small number of families, compared with 10 ³ or greater for Igs (see later discussion). The principles governing generation of diversity in the TCR are very similar to those for Ig genes. T cells can only recognize short peptides that are associated with MHC molecules. In contrast, the Ig receptor can recognize peptides, whole proteins, nucleic acids, lipids, and small chemicals.

T cells also express a variety of nonpolymorphic antigens on their surfaces. The most abundantly expressed is CD45, comprising 10% of lymphocyte membrane proteins. CD45 exists as a number of isoforms that differ in the molecular weight of their extracellular domains as a result of RNA splicing. These isoforms can be distinguished serologically. The low molecular weight (CD45RO) isoforms define activated, or memory, T-cell populations.

B Lymphocytes

B cells are the precursors of antibody-secreting cells. The cells develop in the bone marrow and during their ontogeny acquire Ig receptors that commit them to recognizing specific antigens for the rest of their lives. B cells normally express IgM on their cell surfaces but switch to other isotypes as a consequence of T-cell help, while maintaining antigen specificity (see later discussion). Following antigenic challenge, T lymphocytes assist (help) B cells directly (cognate interaction) or indirectly by secreting helper factors (noncognate interaction) to differentiate and form mature antibody-secreting plasma cells.

Immunoglobulins

Immunoglobulins are glycoproteins that are the secretory product of plasma cells. Their biochemical structure and genomic organization are shown in Fig. 49.1 . All Ig molecules share a number of common features. Each molecule consists of two identical polypeptide light chains (kappa [κ] or lambda [λ]) linked to two identical heavy chains. The light and heavy chains are stabilized by intrachain and interchain disulfide bonds. According to the biochemical nature of the heavy chain, Igs are divided into five main classes: IgM, IgD, IgG, IgA, and IgE. These may be further divided into subclasses depending on differences in the heavy chain.

Each heavy and light chain consists of variable and constant regions. The amino terminus is characterized by sequence variability in both the light and the heavy chain, and each variable heavy- and light-chain unit acts as the antigen-binding site (the Fab portion). The carboxy terminal of the heavy chain (also known as the Fc portion ) is involved in binding to host tissue and fixing complement. This part of the molecule is important for antibody-dependent, cell-mediated cytotoxicity by cells of the reticuloendothelial system and for complement-mediated cell lysis.

Classes of Igs differ in their ability to fix complement. In humans, IgM, IgG1, and IgG3 antibodies are capable of activating the complement cascade. Different Ig classes also differ in their transport properties and ability to bind to phagocytes. Fc binding to Fc receptors (FcRs) present on macrophages, dendritic cells, neutrophils, NK cells, and B cells initiates signaling within the cell only when the receptors are cross-linked by immune complexes containing more than one IgG molecule. Different FcRs mediate different cellular responses, some being predominantly stimulatory, while others are inhibitory.

Antigen Receptor Gene Rearrangements

During B- and T-cell development, multiple gene rearrangements occur to form their respective antigen receptors, the Ig and the TCR. Diversity of the antigen receptors is due to diversity in their principal components, the V gene segment and the J gene segments. One of the many V gene segments is juxtaposed by chromosomal rearrangements with one of the J segments (and when present, with the diversity [D] segment) to form the complete variable region gene. Recombinational inaccuracies at the joining sites of the V, D, and J regions further increase the diversity of the antigen receptors.

C gene segments are present in all receptors. The V, D, J, and C gene segments along with the intervening noncoding gene segments between the J and C regions are initially transcribed into mature RNA. Through a process of RNA splicing, the noncoding gene segments are excised, and the V(D)JC messenger RNA (mRNA) is translated into protein. After binding antigen, B cells undergo somatic mutations that further increase the diversity and the affinity of antigen binding (affinity maturation). This phenomenon does not occur in T cells. During isotype switching in B cells, further rearrangements lead to recombination of the same variable region gene with new constant region genes (see Fig. 49.1 ).

Major Histocompatibility and Human Leukocyte Antigens

MHC gene products or the human leukocyte antigens (HLAs) serve to distinguish self from nonself. In addition, they serve the important function of presenting antigen to the appropriate cells. The MHC class I gene product contains an MHC-encoded α chain, and a smaller non-MHC-encoded β ₂ -microglobulin chain. The MHC class II gene product consists of two polypeptide chains, α and β, which are noncovalently linked. Both class I and class II proteins are stabilized by intrachain disulfide bonds. Class I antigens are expressed on all nucleated cells, whereas class II antigens are constitutively expressed only on dendritic cells, macrophages, and B cells, and are expressed on a variety of activated cells including T cells, endothelial cells, and astrocytes.

In humans, class I molecules are HLA-A, B, and C, whereas the class II molecules are HLA-DP, DQ, and DR. Several alleles are recognized for each locus; thus the HLA-A locus has at least 20 alleles, and HLA-B has at least 40. The number of alleles for the D region appears to be as extensive as that for HLA-A, HLA-B, and HLA-C. In view of the extensive polymorphisms present, the chances of two unrelated individuals sharing identical HLA antigens are extremely low. The reason for the extensive diversity and evolutionary pressure that lead to this are not fully understood.

Class I antigens regulate the specificity of cytotoxic CD8 ⁺ T cells, which are responsible for killing cells bearing viral antigens or foreign transplantation antigens ( Fig. 49.2 ). The target cells share class I MHC genes with the cytotoxic cell. Thus the cytotoxic cell that is specific for a particular virus is capable of recognizing the antigenic determinants of the virus only in association with a particular MHC class I gene product. The function of class II MHC gene products appears to be to regulate the specificity of T-helper cells, which in turn regulate DTH and antibody response to foreign antigens. Similarly, an immunized T-cell population will recognize a foreign antigen only if it is presented on the surface of an APC that shares the same class II MHC antigen specificity as the immunized T-cell population. Thus the functional specificity of the T-cell population is restricted by the MHC molecules they recognize. CD8 ⁺ T cells (cytotoxic) and CD4 ⁺ T cells (helper) are referred to as MHC class I and MHC class II restricted T cells , respectively ( Fig. 49.3 ).

The analysis of the three-dimensional structure of the class I and class II molecules has confirmed the notion that these molecules are carriers of immunogenic peptides that are processed by APCs and presented on the cell surface ( Fig. 49.4 ). Both MHC class I and class II molecules share similarities in crystal structure that allow them to accept and retain immunogenic peptides in grooves, or pockets, and present them to T cells.

Antigen Presentation

One of the crucial initial steps in the immune response is the presentation of encountered antigens to the immune system. Antigens are carried from their site of arrival in the periphery by way of lymphatics or blood vessels to the lymph nodes and spleen. There, antigens are then taken up by cells of the monocyte-macrophage lineage and by B cells, processed intracellularly, and presented not as whole molecules but as highly immunogenic peptides.

Accessory Molecules for T-Cell Activation

The interaction of MHC-peptide complex with T cells, although necessary, is insufficient for T-cell activation. Other classes of molecules are involved in T-cell antigen recognition, activation, intracellular signaling, adhesion, and trafficking of T cells to their target organs. The distinction between the functions of these classes of molecules is not absolute, and many may be involved in interactions between other cells of the immune system.