91731_ch04 12/8/06 7:38 PM Page 99 Built By: jerry/CHEY QC’ed By: Corrected By: LP-QPC-91731 Chapter 4 Please Delete Before Going to Printer 4 Immunopathology Jeffrey S. Warren Douglas P. Bennett Roger J. Pomerantz Biology of the Immune System Combined Immunodeficiency Diseases Cellular Components of the Immune System Wiskott-Aldrich Syndrome The Major Histocompatibility Complex (MHC) Autoimmunity and Autoimmune Diseases Integrated Cellular and Humoral Immune Responses Autoimmune Disease and Immunologic Tolerance Clinical Evaluation of Immune Status Systemic Lupus Erythematosus (SLE) Immunoglobulin Concentrations Lupus-like Diseases Antibody-Dependent Immunity Sjögren Syndrome Cell-Mediated Immunity Scleroderma (Progressive Systemic Sclerosis) Lymphocyte Populations Mixed Connective Tissue Disease Molecular Diagnostic Studies Immune Reactions to Transplanted Tissues AQ1 Immunologically Mediated Tissue Injury Hyperacute Rejection AU 1 IgE-Mediated Immediate Hypersensitivity Reactions Acute Rejection AU 2 AU 6 (Type I) Chronic Rejection AQ3 AU 3 Non–IgE Antibody-Mediated Hypersensitivity Reaction Graft-versus-Host Disease AU 4 (Type II) Human Immunodeficiency Virus (HIV) Infection and Cell-Mediated Immune Complex Reactions (Type III) Acquired Immunodeficiency Syndrome (AIDS) AU 7 Hypersensitivity Reactions (Type IV) Transmission AQ4 Immunodeficiency Diseases HIV-1 Primary Antibody Deficiency Diseases Opportunistic Infections Primary T Cell Immunodeficiency Diseases HIV-2 AQ2AU 5 he most basic challenge to an organism is to distinguish self Chapter 2). Host defenses that are not antigen-specific are called from nonself so that it can continue to exist. The chief role the “innate” immune system. Antigen-specific or “adaptive” Tof the immune system is to protect the host from invasion immune system encompasses lymphocytes, plasma cells, anti- by foreign agents. Immune responses can be elicited by a wide gen-presenting cells (APCs), specific effector molecules (e.g., im- range of agents including parasites, bacteria, viruses, chemicals, munoglobulins), and a vast array of regulatory mediators. toxins, drugs, and transplanted tissues. As components of host As noted above, the defining features of adaptive immunity defense, immune responses are characterized by their ability to include specificity, memory, and the capacity for amplification. distinguish self from nonself, their ability to discriminate among Specificity and immunologic memory are direct results of acti- potential invaders (specificity), and immune memory, coupled vation by antigens of lymphocyte clones that bear specific recep- to the capacity for amplification (i.e., the ability to recall previ- tors. There are many linkages among the various layers of host ous exposures and to mount an intensified or anamnestic defense. For example, an antibody can specifically bind to an epi- response). tope on a bacterium, leading to complement fixation, and, in Humans possess physical barriers such as regionally adapted turn, generation of chemotactic peptides that attract phagocytic epithelia (e.g., thick skin, ciliated respiratory epithelium, and a neutrophils. nearly impervious urothelium), chemical–mechanical barriers It is important to consider the relationships of specific im- (e.g., antibacterial lipids and mucus), and indigenous microbial mune system components within the general rubric of acute and flora that compete with potential pathogens. Patterned hemo- chronic inflammation, cell injury, and cell death. For example, dynamic responses, cell surface-associated and soluble mediator immediate (type I) hypersensitivity reactions are immunoglobu- systems (e.g., complement and coagulation systems), and anti- lin (Ig)E-mediated, depend on generation of vasoactive com- gen-nonspecific phagocytes (e.g., resident macrophages, neu- pounds, and feature inflammatory infiltrates rich in eosinophils. trophils) are integral to protective inflammatory responses (see A type III hypersensitivity reaction, which is immune complex- 99 91731_ch04 12/8/06 7:38 PM Page 100 100 Pathology mediated, is characterized by an acute inflammatory infiltrate activation antigens, and in terms of their capacity to engraft bone (mainly neutrophils). Type IV hypersensitivity reactions are trig- marrow. Infusion of peripheral blood HSCs in sufficient num- gered by antigen exposure and involve chronic inflammatory in- bers into transplant recipients leads to faster marrow recovery filtrates (mononuclear phagocytes and T lymphocytes). Recog- than occurs in patients who have received marrow-derived nition of these mechanistic and morphologic relationships can HSCs. HSCs are quantified following harvest and before infusion be helpful diagnostically and therapeutically. into recipient patients. In clinical HSC transplantation, it is now common practice for donors to receive recombinant growth fac- tors prior to HSC harvest. This practice has led to higher yields Biology of the Immune System of harvested HSCs, decreased time to engraftment, and im- The Cells that Comprise the Immune System Derive from proved rates of successful engraftment. The proportion of bone Hematopoietic Stem Cells marrow transplant recipients who receive harvested peripheral blood HSCs rather than marrow-derived HSCs has increased The cellular components of the immune system are derived dramatically in recent years. from pluripotent hematopoietic stem cells (HSCs). Near the end of the first month of embryogenesis, HSCs appear in the ex- Lymphopoiesis and Hematopoiesis traembryonic erythropoietic islands adjacent to the yolk sac. At All mature lymphoid and hematopoietic cells are derived from a 6 weeks, the primary site of hematopoiesis shifts from extraem- common population of pluripotential HSCs (Fig. 4-1). Each step bryonic blood islands to fetal liver to bone marrow. The process in lymphopoiesis and hematopoiesis depends on a microenvi- begins at 2 months but by 6 months has completely shifted to ronment that encompasses specific structural features and a bone marrow. Although there are well-defined sequential complex array of growth factors. The primary branch point in changes in the primary site of hematopoiesis, there are periods differentiation is between lymphoid progenitors and myeloid of overlap. By 8 weeks of gestation, lymphoid stem cells derived progenitors. The former ultimately give rise to T lymphocytes, from HSCs and fated to become T cells circulate to the thymus B lymphocytes, and natural killer (NK) cells; whereas the latter where they differentiate into mature T lymphocytes. Lymphoid develop into granulocytic, erythroid, monocytic–dendritic, and stem cells destined to become B cells differentiate first within fe- megakaryocytic colony-forming units (GEMM-CFUs). Down- tal liver (8 weeks) and later within bone marrow (12 weeks). In stream, CFUs become more lineage-specific. Examples include the development of both thymic T lymphocytes and bone mar- CFU-GM (granulocyte-monocyte), CFU-Eo (eosinophil), CFU-E row B lymphocytes, the microenvironments (e.g., thymic ep- (erythrocyte), and so forth. CFU refers to a cell that ultimately ithelium, bone marrow stromal cells, growth factors) are critical. gives rise to a specified population of “offspring,” such as granu- Mature lymphocytes exit the thymus and bone marrow and locytes, erythrocytes, monocytes, dendritic cells, and megakary- “home” to peripheral lymphoid tissues (e.g., lymph nodes, ocytes. spleen, skin, and mucosa). The population of peripheral lym- phoid tissues by mature T and B lymphocytes and the rapid de- Lymphocytes ployment and recirculation of mature lymphocytes to different, There are three major types of lymphocytes—T cells, B cells, often remote, parts of the immune system are anatomically spe- and NK cells—which account for 25% of peripheral blood leuko- cific. “Lymphocyte homing and recirculation” are orchestrated cytes. Some 80% of blood lymphocytes are T cells, 10% B cells, by a series of leukocyte and endothelial surface molecules called and 10% NK cells. The relative proportions of lymphocytes in selectins and addressins. The processes of lymphocyte devel- the peripheral blood and central and peripheral lymphoid tissues opment and homing/recirculation are important for under- vary. In contrast to the blood, only 30% to 40% of splenic and standing immune responses, genetic immunodeficiency states, bone marrow lymphocytes are T cells. regional host defense, and the underpinnings of modern thera- T lymphocytes can be subdivided into subpopulations by peutics (e.g., HSC transplantation). virtue of their specialized functions, by surface CD molecules, The cells of the immune system express a vast array of surface and in some cases, morphologic features. Lymphoid progenitor molecules that are important in cellular differentiation and cell-to- cells destined to become T cells exit the bone marrow and mi- cell communication. These surface molecules serve as useful grate to the thymus in waves. There, both alpha/beta (␣/␤) and markers of cellular identity. The International Workshop on Hu- gamma/delta (␥/␦) T lymphocytes are formed (Fig. 4-2). “Al- man Leukocyte Differentiation Antigens is responsible for pha/ beta” and “gamma/delta” are the two major classes of het- nomenclature of these markers and assigns them so-called cluster erodimeric T cell receptors (TCRs) that specifically recognize of differentiation or cluster designation (CD) numbers. Currently, and bind various antigens. The thymic microenvironment is de- some 300 different molecules have