Immunology for the Primary Care Physician
Mary K. Crow
The function of the immune system is to limit damage to the host by micro-organisms. The immune response to an infection has two components:
The innate immune response is the earliest phase of an immune response, triggered by microbial components such as lipopolysaccharide (LPS), heat shock proteins, bacterial DNA, and viral double-stranded (ds) RNA. It comprises phagocytes, including macrophages and neutrophils; natural killer (NK) cells; natural antibodies; soluble molecules, such as cytokines, chemokines, and immunomodulatory molecules (e.g., prostaglandins); and the complement system. Activation of the innate immune response is mediated by interaction of microbial components with members of the Toll-like receptor (TLR) family. A close connection exists between the innate and adaptive immune systems via interferon-α This is an important concept because it is possible that an infection triggers an autoimmune disorder through this mechanism.
The adaptive immune response develops several days after the initiation of a primary immune response and is mediated by lymphocytes expressing cell membrane receptors specific to the invading pathogen. Adaptive immunity is characterized by an increase in antigen specificity over time and development of immunologic memory.
Specificity. Individual T and B lymphocytes bear cell surface receptors that recognize a defined molecular structure (epitope) on an antigen (i.e., a molecule on or in a bacterium or virus, or a peptide, that elicits an immune response). Each lymphocyte expresses a single receptor of unique structure and antigenic specificity.
T-cell receptors (TCRs) do not change upon antigen exposure, but B cells can modify their cell surface immunoglobulin (Ig) by somatic mutation.
Memory. Reintroduction of an antigen elicits an immune response more rapidly, and of greater magnitude, than that which occurred on initial exposure.
CELLULAR AND MOLECULAR COMPONENTS OF THE IMMUNE RESPONSE
The central players in the generation of an adaptive immune response include an antigen, an antigen-presenting cell (APC), an antigen-specific T lymphocyte, and a B lymphocyte capable of differentiation into a plasma cell that can secrete an antigen-specific Ig (antibody). Arguably, the most important structure in the immune system in terms of generation of a specific immune response is the trimolecular complex that includes the following:
Major histocompatibility complex (MHC) molecule on the surface of an APC.
APCs are located at many sites throughout the body, especially skin, mucosal surfaces, lymph nodes, spleen, and liver. They are among the first cells to encounter infectious organisms. All APCs express cell surface MHC class I and II molecules.
Types of APC
Activated B lymphocytes specifically bind and process antigen via surface immunoglobulin (sIg) receptors or bind antigen-containing immune complexes via sIg reactive with the constant region of IgG (i.e., sIg with rheumatoid factor activity).
Monocytes/Macrophages bind and phagocytose intact or fragmented micro-organisms, particulate or soluble antigens, or immune complexes via receptors for the Fc fragment of IgG or receptors for complement components (C4b/C3b and iC3b).
Dendritic cells are the most potent APCs because they express higher levels of MHC class II molecules and costimulatory (CD80, CD86) and adhesion [intercellular cell adhesion molecule-1 (ICAM-1)] molecules than other APCs. They have a capacity for “macropinocytosis”—“drinking” of the surrounding molecular constituents––and antigen processing. Dendritic cells can engulf apoptotic virus-infected cells and present the viral antigens to both CD4+ and CD8+ positive T cells. Follicular dendritic cells in lymphoid organs (a distinct cell type) may serve as a reservoir for presentation of preprocessed antigenic peptides to B cells. There are several subtypes of dendritic cells that may mediate different functions. Some derive from the myeloid lineage and others from the lymphoid lineage.
Activation of an APC occurs through uptake of antigen [through sIg or Fc receptor (FcR)], binding of microbial products to TLR, and binding of cytokines released after activation of the innate immune response [interferon-α (INF-α), tumor necrosis factor-α (TNF-α)]. APCs are also activated by cell-mediated interactions with activated T cells (through CD40) and by T-cell–derived cytokines, such as interferon-γ
Function of APC
Antigens generated in the intracellular compartment (e.g., virus-encoded proteins) are processed by enzymatic digestion in a “proteosome,” chaperoned to the endoplasmic reticulum by members of the heat shock protein family of molecules, and incorporated into the binding site of MHC class I molecules as small peptides of approximately nine amino acids in length. These MHC class I-bound peptides are presented to CD8+ T cells.
Antigens taken in from the extracellular environment are enzymatically processed in specialized intracellular compartments enriched in MHC class II molecules. Antigenic peptides of variable length (13 to 18 amino acids) in the class II antigen-binding cleft are transported to the cell surface. These MHC class II-bound peptides are presented to CD4+ T cells.
Poorly understood intracellular processes favor the enzymatic cleavage and presentation of particular amino acid sequences within an antigen. This concept is termed “determinant selection.” B cells that are activated by specific antigens
can take up those antigens through sIg and present a different set of epitopes than dendritic cells or monocytes. Presentation of such “cryptic” epitopes may break tolerance and lead to autoimmunity.
Dendritic cells can be “matured” by IFN-α or TNF-α thereby increasing their capacity to activate T cells.
Activated APCs secrete cytokines, including IL-1, IL-12, TNF-α and transforming growth factor-β (TGF-β), that help regulate the character of the T-cell response to antigen.
T Lymphocytes are the central regulatory cell in the immune system. Functional T-cell subsets include T helper cells, which produce either T helper 1 (TH1) or T helper 2 TH2 cytokines and which support B cell, macrophage, or dendritic cell differentiation, or T cytotoxic/suppressor cells, which mediate death of target cells.
Location. Maturation and selection of the T-cell repertoire occurs in the thymus, whereas mature T cells are found in skin, lymph nodes, spleen, gut, lymph, and blood. Memory T cells may have different homing patterns than naïve T cells that have not been stimulated by antigens.
TCR complex. Most T cells express a TCR heterodimer composed of α and β chains. These chains contain constant and variable regions. The variable region of a given TCR-α or TCR-β chain is encoded by one of a number of variable genes, each characterized by particular nucleotide sequences. Variability among TCR is derived from transcription of different variable genes, insertions and deletions of nucleotides in the TCR chains, and variable pairing of α and β chains. The complementarity determining region 3 (CDR3) of the TCR chains constitutes the TCR structure that interacts with antigenic peptide in the MHC class I or II binding sites. A small T-cell population expresses a TCR heterodimer composed of γ and δ chains.
The CD3 molecule is composed of five chains that associate with the TCR in the T-cell membrane. It transduces activation signals to the T cell by triggering biochemical pathways, including protein kinases.
Subset markers on the surface of T lymphocytes
CD4 is on 60% to 70% of T cells; it associates with MHC class II molecules on APC; and its expression correlates with helper/inducer function (meaning helping or inducing B cells to produce antibodies), although some CD4+ T cells can mediate cytotoxicity (meaning cell killing) through Fas ligand–Fas receptor interactions.
CD8 is on 30% to 40% of T cells; it associates with MHC class I molecules on APC; and its expression correlates with cytotoxic/suppressor function (i.e., cell killing or suppression of an immune response).
Accessory and costimulatory molecules that mediate binding to other cells and transmit activation or inhibitory signals
CD2 and lymphocyte function-associated antigen (LFA-1) are adhesion molecules.
CD28 ligation by CD80 or CD86 results in a T-cell stimulatory signal that augments TCR-mediated T-cell activation.
CTLA-4 ligation by CD80 or CD86 leads to inhibitory signals to the T cell.
ICOS is a CD28-like molecule that appears to preferentially costimulate TH2-like responses and memory T cells. Its ligand is B7RP-1.
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