CHAPTER 16 IMMUNOLOGY Brad Frankum, Monique Wei Meng Lee and Jessie A Lee –Sjögren’s syndrome (SS) CHAPTER OUTLINE –Infl ammatory myopathies –Anti-synthetase syndrome • KEY CONCEPTS IN IMMUNOBIOLOGY –Scleroderma and CREST syndrome – Innate and adaptive immunity –Mixed connective tissue disease (MCTD) –Specifi city and diversity –Antiphospholipid syndrome (APS) –Immunological memory – IgG4-related disease –Hypersensitivity, autoimmunity and immunodefi ciency • PRIMARY VASCULITIS – Immunity, infl ammation and tissue repair – Large-vessel vasculitis –Understanding immunobiology –Medium-vessel vasculitis – Manipulation of the immune system –Small-vessel vasculitis – Single-organ vasculitis • ALLERGIC DISEASE –Variable-vessel vasculitis –Anaphylaxis – Allergic rhinitis (AR) and allergic • AUTOINFLAMMATORY DISORDERS conjunctivitis (AC) – Familial Mediterranean fever (FMF) –Chronic rhinosinusitis – TNF-receptor-associated periodic syndrome – Atopic dermatitis (AD) (TRAPS) – Food allergy • IMMUNODEFICIENCY –Urticaria and angioedema – Drug allergy –Primary immunodefi ciency – Insect venom allergy –Secondary (acquired) immunodefi ciency • EOSINOPHILIA • HIV/AIDS –Hypereosinophilic syndrome (HES) –Epidemiology – Risk factors for HIV infection • MAST CELL DISORDERS – Pathophysiology –Cutaneous mastocytosis (CM) – Clinical features and diagnosis –Systemic mastocytosis (SM) –Management –Prognosis • SYSTEMIC AUTOIMMUNE DISEASE – Systemic lupus erythematosus (SLE) 507 Essentials of internal medicine KEY CONCEPTS IN mechanisms such as coughing, sneezing, urination, and mucus production. IMMUNOBIOLOGY • The innate immune response is rapid, fi rst- line, and prevents tissue invasion in most instances. • Innate and adaptive immunity are unique but heavily interdependent entities. • Epithelial surfaces also provide chemical barriers to infection in the form of secreted antimicrobial peptides, • Specifi city and diversity are the foundation for success- antibacterial enzymes and fatty acids, as well as microbio- ful adaptive immunity. logical barriers in the form of commensal microbiota that • Immunological memory is the basis for immunity and compete with pathogens. immunization. • Phagocytic cells can recognize a restricted number of • Hypersensitivity, autoimmunity and immuno defi ciency cell- surface molecules on microbial pathogens, and are the key drivers of immunopathology. be directly activated. These molecules are known as • Immunity, infl ammation and tissue repair are essential pathogen- associated molecular patterns (PAMPs). and interdependent components of a complex system to Examples of receptors that can recognize PAMPs include maintain health. Toll- like receptors, and mannose- binding lectin (MBL). • Understanding immunobiology is the key to logical • There are also receptors in the cytoplasm of cells that can diagnosis and treatment of infection. recognize microbial products. This is obviously important • Manipulation of the immune system is central to the for dealing with pathogens that have evaded defense mech- current, and future, treatment of a vast range of human anisms in the extracellular environment. Examples include diseases: allergy, autoimmunity, malignancy, infection NOD- like and RIG- 1- like receptors and MDA-5. and transplantation. • The innate immune system also recognizes molecules released from damaged or infected cells. These mol- Innate and adaptive immunity ecules are known as DAMPs, or damage- associated Innate and adaptive immunity are unique but heavily inter- molecular patterns. dependent entities. Their key features are described in » DAMPs help to activate both the innate immune Table 16- 1. response and the infl ammatory response. • Complement is a set of plasma proteins that form a cas- Innate immune response cade to ensure amplifi cation of both innate and adaptive Innate immunity refers to that section of the immune system immune responses. that does not require specifi c antigen recognition to elimi- » Complement can be activated by the presence of nate a pathogen. It includes barrier functions such as integ- microbial cell surfaces, by the presence of immune rity of the skin and mucous membranes, and physiological complexes, or by the binding of MBL. Table 16-1 Innate versus adaptive immunity KEY FEATURES INNATE IMMUNE SYSTEM ADAPTIVE IMMUNE SYSTEM Cells Neutrophils, monocyte-macrophages, eosinophils, B and T lymphocytes, plasma cells basophils, mast cells, dendritic cells, natural killer cells Receptors PRRs, Toll-like receptors B-cell receptors (immunoglobulins), T-cell receptors Eff ectors Molecular—complement, acute phase reactants, cytokines Humoral—B cells, antibody Cellular—phagocytes (neutrophils, monocyte- Cell-mediated—cytotoxic T cells macrophages), cells that produce infl ammatory mediators (eosinophils, basophils, mast cells), natural killer cells Specifi city Absent Antigen-specifi c Memory Absent (does not require prior contact) Antigen-specifi c (requires prior contact) Response time Immediate Delayed Response Not enhanced by prior contact Enhanced by prior contact magnitude PRR, pattern-recognition receptor. 508 Chapter 16 Immunology » Activated complement proteins have chemotactic actions to trigger phagocytosis, as well as eff ector Box 16-1 function, resulting in cell killing through the mem- The fi ve stages of the adaptive brane attack complex. immune response Activation of the innate immune response results in recruit- ment of the adaptive response. This is achieved predominantly 1 Antigen capture via antigen presentation by dendritic cells and macrophages to 2 Recognition of antigen lymphocytes, but is augmented by changes in cytokine milieu. 3 Activation of lymphocytes In turn, the adaptive immune response utilizes eff ector cells of the innate system. 4 Antigen elimination 5 Decline of immune response Adaptive immune response The three key components of the adaptive immune response are diversity, specifi city and memory. » are the cells which recognize self- antigen, so are • Diversity is manifested by the deliberate generation of antigen- specifi c, but develop in such a way as to many lymphocyte clones, but selecting only those that suppress response toward self- antigen rather than recognize foreign but not self- antigen for survival. initiate it • Specifi city refers to each lymphocyte clone having » function to maintain self- tolerance and suppress receptors of one specifi city, and responding to that infl ammatory responses. specifi c antigen only. The adaptive immune response proceeds through the fi ve • Memory is maintained by retention of antigen- specifi c stages listed in Box 16- 1. clones of both B and T lymphocytes, and the ongoing The major histocompatibility complex (MHC) is a set of production of specifi c antibody, in perpetuity. genes which encode for cell- surface proteins that represent a critical step in presenting foreign antigen to the eff ector cells A number of diff erent cells are involved (Figure 16- 1): of the immune system. • B cells diff erentiate into plasma cells to secrete antibody. • Cells which are able to stimulate CD8+ cytotoxic T • CD4+ T- helper cells direct other cells to perform cells must be able to process cytosolic antigen, and pres- eff ector functions. ent the antigen to the cell surface in conjunction with • CD8+ cytotoxic T cells, when activated, kill cells MHC class I antigens. These are all nucleated cells. infected by intracellular organisms, e.g. viruses. • Cells which are able to present antigen to CD4+ T- helper • T- regulatory cells: cells, and stimulate them, must be able to process endo- » are a subset of CD4+ T cells which express high lev- cytosed antigen, and express MHC class II antigens els of CD25, and a transcription factor called FoxP3 in conjunction with the foreign antigen on the cell sur- » are generated centrally in the thymus, or peripher- face. These are dendritic cells, monocyte-macrophages ally in secondary lymphoid tissue and B lymphocytes, and are collectively referred to as antigen- presenting cells. Specifi city and diversity Specifi city and diversity are the foundation for successful Adaptive adaptive immunity. immune system • During development in the bone marrow (B cells) and the thymus (T cells), millions of diff erent genetic recombinations occur in the genes that encode for lym- APC Lymphocytes phocyte receptors. • Immunological specifi city refers to the ability of the immune system to possess cells that are capable of rec- ognizing one specifi c antigen only. This is the function T cells B cells of the lymphocyte. CD3 CD19, CD20 » B lymphocytes express cell- surface receptor (immu- noglobulin) which is specifi c for one antigen. When secreted, this immunoglobulin can be arranged as a pentamer (IgM), dimer (IgA) or monomer (IgG, T-helper T cytotoxic T reg IgE, IgD), but still remains specifi c for one antigen CD3, CD4 CD3, CD8 only. » T lymphocytes express the T- cell receptor which is Figure 16-1 Cells of the adaptive immune system. also specifi c for one antigen only. APC, antigen-presenting cell; T reg = T-regulatory • Immunological diversity refers to the capacity of cell the immune system to have lymphocytes capable of 509 Essentials of internal medicine recognizing every conceivable antigen. The vastness of –Eff ector T lymphocytes are either cytotoxic this repertoire is staggering. T lymphocytes or T-helper cells. » In generating suffi cient diversity amongst the lym- –Eff ector B lymphocytes are plasma cells, which phocyte population, the immune system needs a secrete antibody. system