Introduction to the Immune System (The Immune System in Health and Disease) (Rheumatology) Part 1

Definitions

•    Adaptive immune system—recently evolved system of immune responses mediated by T and B lymphocytes. Immune responses by these cells are based on specific antigen recognition by clonotypic receptors that are products of genes that rearrange during development and throughout the life of the organism. Additional cells of the adaptive immune system include various types of antigen-presenting cells.

•    Antibody—B cell-produced molecules encoded by genes that rearrange during B cell development consisting of immunoglobulin heavy and light chains that together form the central component of the B cell receptor for antigen. Antibody can exist as B cell surface antigenrecognition molecules or as secreted molecules in plasma and other body fluids (Table 1-11).

•    Antigens—foreign or self-molecules that are recognized by the adaptive and innate immune systems resulting in immune cell triggering, T cell activation, and/or B cell antibody production.

•    Antimicrobialpeptides—small peptides <100 amino acids in length that are produced by cells of the innate immune system and have anti-infectious agent activity (Table 1-2).

•    Apoptosis—the process of programmed cell death where by signaling through various “death receptors” on the surface of cells [e.g., tumor necrosis factor (TNF) receptors, CD95] leads to a signaling cascade that involves activation of the caspase family of molecules and leads to DNA cleavage and cell death. Apoptosis, which does not lead to induction of inordinate inflammation, is to be contrasted with cell necrosis, which does lead to induction of inflammatory responses.

•    B lymphocytes—bone marrow-derived or bursal-equivalent lymphocytes that express surface immunoglobulin (the B cell receptor for antigen) and secrete specific antibody after interaction with antigen (Figs. 1-2,1-6).

•    B cell receptorfor antigen—complex of surface molecules that rearrange during postnatal B cell development, made up of surface immunoglobulin (Ig) and associated Ig αβ chain molecules that recognize nominal antigen via Ig heavy and light chain variable regions, and signal the B cell to terminally differentiate to make antigen-specific antibody (Fig. 1-8).

•    CD classification of human leukocyte differentiation antigens— the development of monoclonal antibody technology led to the discovery of a large number of new leukocyte surface molecules. In 1982, the First International Workshop on Leukocyte Differentiation Antigens was held to establish a nomenclature for cell-surface molecules of human leukocytes. From this and subsequent leukocyte differentiation workshops has come the cluster of differentiation (CD) classification of leukocyte antigens (Table 1-1).

•    Chemokines—soluble molecules that direct and determine immune cell movement and circulation pathways.

•    Complement—cascading series of plasma enzymes and effector proteins whose function is to lyse pathogens and/or target them to be phagocytized by neutrophils and monocyte/macrophage lineage cells of the reticuloendothelial system (Fig. 1-5).

•    Co-stimulatory molecules—molecules of antigen-presenting cells (such as B7-1 and B7-2 or CD40) that lead to T cell activation when bound by ligands on activated T cells (such as CD28 or CD40 ligand) (Fig. 1-7).

•    Cytokines—soluble proteins that interact with specific cellular receptors that are involved in the regulation of the growth and activation of immune cells and mediate normal and pathologic inflammatory and immune responses (Tables 1-6,1-8,1-9).

•    Dendritic cells—myeloid and/or lymphoid lineage antigen-presenting cells of the adaptive immune system. Immature dendritic cells, or dendritic cell precursors, are key components ofthe innate immune system by responding to infections with production of high levels of cytokines. Dendritic cells are key initiators both of innate immune responses via cytokine production and of adaptive immune responses via presentation of antigen to T lymphocytes (Figs. 1-2 and 1-3, Table 1-5).

•    Innate immune system—ancient immune recognition system of host cells bearing germ line-encoded pattern recognition receptors (PRRs) that recognize pathogens and trigger a variety of mechanisms of pathogen elimination. Cells of the innate immune system include natural killer (NK) cell lymphocytes, monocytes/macrophages, dendritic cells, neutrophils, basophils, eosinophils, tissue mast cells, and epithelial cells (Tables 1-2,1-3,1-4,1-5,1-10).

•    Large granular lymphocytes—lymphocytes of the innate immune system with azurophilic cytotoxic granules that have NK cell activity capable of killing foreign and host cells with few or no self-major histocompatibility complex (MHC) class I molecules (Fig. 1-4).

•    Natural killer cells—large granular lymphocytes that kill target cells expressing few or no human leukocyte antigen (HLA) class I molecules, such as malignantly transformed cells and virally infected cells. NK cells express receptors that inhibit killer cell function when self-MHC class I is present (Fig. 1-4).

•    Pathogen-associated molecular patterns (PAMPs)—Invari-ant molecular structures expressed by large groups of microorganisms that are recognized by host cellular pattern recognition receptors in the mediation of innate immunity (Fig. 1-1).

•    Pattern recognition receptors (PRRs)—germ line-encoded receptors expressed by cells of the innate immune system that recognize pathogen-associated molecular patterns (Table 1-3).

•    T cells—thymus-derived lymphocytes that mediate adaptive cellular immune responses including T helper, T regulatory, and cytotoxic T lymphocyte effector cell functions (Figs. 1-2, 1-3,1-6).

•    T cell receptor for antigen—complex of surface molecules that rearrange during postnatal T cell development made up of clonotypic T cell receptor (TCR) α and β chains that are associated with the CD3 complex composed of invariant γ, δ, ε, ζ, and η chains.TCR-α and -β chains recognize peptide fragments of protein antigen physically bound in antigen-presenting cell MHC class I or II molecules, leading to signaling via the CD3 complex to mediate effector functions (Fig. 1-7).

• Tolerance—B and T cell nonresponsiveness to antigens that results from encounter with foreign or self-antigens by B and T lymphocytes in the absence of expression of antigen-presenting cell co-stimulatory molecules. Tolerance to antigens may be induced and maintained by multiple mechanisms either centrally (in the thymus for T cells or bone marrow for B cells) or peripherally at sites throughout the peripheral immune system.

Introduction

The human immune system has evolved over millions of years from both invertebrate and vertebrate organisms to develop sophisticated defense mechanisms to protect the host from microbes and their virulence factors. The normal immune system has three key properties: a highly diverse repertoire of antigen receptors that enables recognition of a nearly infinite range of pathogens; immune memory, to mount rapid recall immune responses; and immunologic tolerance, to avoid immune damage to normal self-tissues. From invertebrates, humans have inherited the innate immune system, an ancient defense system that uses germ line-encoded proteins to recognize pathogens. Cells of the innate immune system, such as macrophages, dendritic cells, and natural killer (NK) lymphocytes, recognize pathogen-associated molecular patterns (PAMPs) that are highly conserved among many microbes and use a diverse set of pattern recognition receptor molecules (PRRs). Important components of the recognition of microbes by the innate immune system include (1) recognition by germ line-encoded host molecules, (2) recognition of key microbe virulence factors but not recognition of self-molecules, and (3) nonrecognition of benign foreign molecules or microbes. Upon contact with pathogens, macrophages and NK cells may kill pathogens directly or, in concert with dendritic cells, may activate a series of events that both slow the infection and recruit the more recently evolved arm of the human immune system, the adaptive immune system.

Adaptive immunity is found only in vertebrates and is based on the generation of antigen receptors on T and B lymphocytes by gene rearrangements, such that individual T or B cells express unique antigen receptors on their surface capable of specifically re cognizing diverse antigens of the myriad infectious agents in the environment. Coupled with finely tuned specific recognition mechanisms that maintain tolerance (nonreactivity) to selfantigens, T and B lymphocytes bring both specificity and immune memory to vertebrate host defenses.

This topic describes the cellular components, key molecules (Table 1-1), and mechanisms that make up the innate and adaptive immune systems, and describes how adaptive immunity is recruited to the defense of the host by innate immune responses. An appreciation of the cellular and molecular bases of innate and adaptive immune responses is critical to understanding the pathogenesis of inflammatory, autoimmune, infectious, and immunodeficiency diseases.

Table 1-1:HUMAN LEUKOCYTE SURFACE ANTIGENS-THE CD CLASSIFICATION OF LEUKOCYTE DIFFERENTIATION ANTIGENS

SURFACE ANTIGEN (OTHER NAMES)	FAMILY	MOLECULAR MASS, kDa	DISTRIBUTION	LIGAND(S)	FUNCTION
CD1a (T6, HTA-1)	Ig	49	CD, cortical thymocytes, Langerhans type of dendritic cells	TCRγδ T cells	CD1 molecules present lipid antigens of intracellular bacteria such as M. leprae and M. tuberculosis to TCRγδ T cells.
CD1b	Ig	45	CD, cortical thymocytes, Langerhans type of dendritic cells	TCRγδ T cells
CD1c	Ig	43	DC, cortical thymocytes, subset of B cells, Langerhans type of dendritic cells	TCRγδ T cells
CD1d	Ig	?	Cortical thymocytes, intestinal epithelium, Langerhans type of dendritic cells	TCRγδ T cells
CD2 (T12, LFA-2)	Ig	50	T, NK	CD58, CD48, CD59, CD15	Alternative T cell activation, T cell anergy, T cell cytokine production, T- or NK-mediated cytolysis, T cell apoptosis, cell adhesion
CD3 (T3, Leu-4)	Ig	γ:25-28, δ:21-28, ε:20-25, η:21-22, ζ:16	T	Associates with the TCR	T cell activation and function; ζ is the signal transduction components of the CD3 complex
CD4 (T4, Leu-3)	Ig	55	T, myeloid	MHC-II, HIV, gp120, IL-16, SABP	T cell selection, T cell activation, signal transduction with p56lck, primary receptor for HIV
CD7 (3A1, Leu-9)	Ig	40	T, NK	K-12 (CD7L)	T and NK cell signal transduction and regulation of IFN-γ, TNF-α production
CD8 (T8, Leu-2)	Ig	34	T	MHC-I	T cell selection, T cell activation, signal transduction with p56lck
CD14 (LPS-receptor)	LRG	53-55	M, G (weak), not by myeloid progenitors	Endotoxin (lipopolysaccha-ride), lipoteichoic acid, PI	TLR4 mediates with LPS and other PAMP activation of innate immunity
CD19 (B4)	Ig	95	B (except plasma cells), FDC	Not known	Associates with CD21 and CD81 to form a complex involved in signal transduction in B cell development, activation, and differentiation
CD20 (B1)			B (except plasma cells)	Not known	Cell signaling, may be important for B cell activation and proliferation
CD21 (B2, CR2, EBV-R, C3dR)	RCA	145	Mature B, FDC, subset of thymocytes	C3d, C3dg, iC3b, CD23, EBV	Associates with CD19 and CD81 to form a complex involved in signal transduction in B cell development, activation, and differentiation; Epstein-Barr virus receptor

HUMAN LEUKOCYTE SURFACE ANTIGENS-THE CD CLASSIFICATION OF LEUKOCYTE DIFFERENTIATION ANTIGENS
SURFACE ANTIGEN (OTHER NAMES)	FAMILY	MOLECULAR MASS, kDa	DISTRIBUTION	LIGAND(S)	FUNCTION
CD22 (BL-CAM)	Ig	130-140	Mature B	CDw75	Cell adhesion, signaling through association with p72s^y, p53/56lyn, PI3 kinase, SHP1, fLCy
CD23 ^RII, B6, Leu-20, BLAST-2)	C-type lectin	45	B, M, FDC	IgE, CD21, CD11b, CD11c	Regulates IgE synthesis, cytokine release by monocytes
CD28	Ig	44	T, plasma cells	CD80, CD86	Co-stimulatory for T cell activation; involved in the decision between T cell activation and anergy
CD40	TNFR	48-50	B, DC, EC, thymic epithelium, MP, cancers	CD154	B cell activation, proliferation, and differentiation, formation of GCs, isotype switching, rescue from apoptosis
CD45 (LCA, T200, B220)	PTP	180, 200, 210, 220	All leukocytes	Galectin-1, CD2, CD3, CD4	T and B activation, thymocyte development, signal transduction, apoptosis
CD45RA	PTP	210, 220	Subset T, medullary thymocytes, “naïve” T	Galectin-1, CD2, CD3, CD4	Isoforms of CD45 containing exon 4 (A), restricted to a subset of T cells
CD45RB	PTP	200, 210, 220	All leukocytes	Galectin-1, CD2, CD3, CD4	Isoforms of CD45 containing exon 5 (B)
CD45RC	PTP	210, 220	Subset T, medullary thymocytes, “naïve” T	Galectin-1, CD2, CD3, CD4	Isoforms of CD45 containing exon 6 (C), restricted to a subset of T cells
CD45RO	PTP	180	Subset T, cortical thymocytes, “memory” T	Galectin-1, CD2, CD3, CD4	Isoforms of CD45 containing no differentially spliced exons, restricted to a subset of T cells
CD80 (B7-1, BB1)	Ig	60	Activated B and T, MP, DC	CD28, CD152	Co-regulator of T cell activation; signaling through CD28 stimulates and through CD152 inhibits T cell activation
CD86 (B7-2, B70)	Ig	80	Subset B, DC, EC, activated T, thymic epithelium	CD28, CD152	Co-regulator of T cell activation; signaling through CD28 stimulates and through CD152 inhibits T cell activation
CD95 (APO-1, Fas)	TNFR	135	Activated T and B	Fas ligand	Mediates apoptosis
CD152 (CTLA-4)	Ig	30-33	Activated T	CD80, CD86	Inhibits T cell proliferation
CD154 (CD40L)	TNF	33	Activated CD4+ T, subset CD8+ T, NK, M, basophil	CD40	Co-stimulatory for T cell activation, B cell proliferation and differentiation

Note: CTLA, cytotoxic T lymphocyte-associated protein; DC, dendritic cells; EBV, Epstein-Barr virus; EC, endothelial cells; ECM, extracellular matrix; Fcy RIIIA, low-affinity IgG receptor isoform A; FDC, follicular dendritic cells; G, granulocytes; GC, germinal center; GPI, glycosyl phos-photidylinositol; HTA, human thymocyte antigen; IgG, immunoglobulin G; LCA, leukocyte common antigen; LPS, lipopolysaccharide; MHC-I, major histocompatibility complex class I; MP, macrophages; Mr, relative molecular mass; NK, natural killer cells; P, platelets; PBT, peripheral blood T cells; PI, phosphotidylinositol; PI3K, phosphotidylinositol 3-kinase; PLC, phospholipase C; PTP, protein tyrosine phosphatase; TCR, T cell receptor; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor. For an expanded list of cluster of differentiation (CD) human antigens, see Harrison’s Online at http://harrisons.accessmedicine.com; and for a full list of CD human antigens from the most recent Human Workshop on Leukocyte Differentiation Antigens (VII), see http://www.ncbi.nlm.nih.aov/prow/auide.

The Innate Immune System

All multicellular organisms, including humans, have developed the use of a limited number of germ line-encoded molecules that recognize large groups of pathogens. Because of the myriad human pathogens, host molecules of the human innate immune system sense “danger signals” and either recognize PAMPs, the common molecular structures shared by many pathogens, or recognize host cell molecules produced in response to infection such as heat shock proteins and fragments of the extracellular matrix. PAMPs must be conserved structures vital to pathogen virulence and survival, such as bacterial endotoxin, so that pathogens cannot mutate molecules of PAMPs to evade human innate immune responses. PRRs are host proteins of the innate immune system that recognize PAMPs or host danger signal molecules (Tables 1-2, 1-3). Thus, recognition of pathogen molecules by hematopoietic and non-hematopoietic cell types leads to activation/production of the complement cascade, cytokines, and antimicrobial peptides as effector molecules. In addition, pathogen PAMPs and host danger signal molecules activate dendritic cells to mature and to express molecules on the dendritic cell surface that optimize antigen presentation to respond to foreign antigens.

TABLE 1-2

MAJOR COMPONENTS OF THE INNATE IMMUNE SYSTEM
Pattern recognition receptors (PRR)	C type lectins, leucine-rich proteins, scavenger receptors, pentraxins, lipid transferases, integrins
Antimicrobial peptides	α-Defensins, ß-defensins, cathelin, protegrin, granulsyin, histatin, secretory leukoprotease inhibitor, and probiotics
Cells	Macrophages, dendritic cells, NK cells, NK-T cells, neutrophils, eosinophils, mast cells, basophils, and epithelial cells
Complement components	Classic and alternative complement pathway, and proteins that bind complement components
Cytokines	Autocrine, paracrine, endocrine cytokines that mediate host defense and inflammation, as well as recruit, direct, and regulate adaptive immune responses

Note: NK cells, natural killer cells.

TABLE 1-3

MAJOR PATTERN RECOGNITION RECEPTORS (PRR) OF THE INNATE IMMUNE SYSTEM
PRR PROTEIN FAMILY	SITES OF EXPRESSION	EXAMPLES	LIGANDS (PAMPS)	FUNCTIONS OF PRR
Toll-like receptors	Multiple cell types	TLR2-10	(see Fig. 1-1 and Table 1-4) Bacterial and viral carbohydrates	Activate innate immune cells to respond to multiple pathogens and initiate adaptive immune responses.
C-type lectins	Plasma proteins	Collectins	Terminal mannose	Opsonization of bacteria and virus, activation of complement
Humoral	Macrophages, dendritic cell	Macrophage mannose receptor	Carbohydrate on HLA molecules	Phagocytosis of pathogens
Cellular	Natural killer (NK) cells	NKG2-A		Inhibits killing of host cells expressing HLA+ self peptides
Leucine-rich proteins	Macrophages, dendritic cells, epithelial cells	CD14	Lipopolysaccharide (LPS)	Binds LPS and Toll proteins
Scavenger receptors	Macrophage	Macrophage scavenger receptors	Bacterial cell walls	Phagocytosis of bacteria
Pentraxins	Plasma protein	C-creative proteins	Phosphatidyl choline	Opsonization of bacteria, activation of complement
	Plasma protein	Serum amyloid P	Bacterial cell walls	Opsonization of bacteria, activation of complement
Lipid transferases	Plasma protein	LPS binding protein	LPS	Binds LPS, transfers LPS to CD14
Integrins	Macrophages, dendritic cells, NK cells	CD11b,c; CD18	LPS	Signals cells, activates phagocytosis

Note: PAMPs, pathogen-associated molecular patterns.