diseases of immune system

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Chapter 6 Diseases of the Immune System

The Normal Immune Response

Innate Immunity

Adaptive Immunity

Components of the Immune System: Cells, Tissues, and Selected Molecules

Cells of the Immune System

Tissues of the Immune System

MHC Molecules: Peptide Display System of Adaptive Immunity

Cytokines: Messenger Molecules of the Immune System

Overview of Lymphocyte Activation and Immune Responses

The Display and Recognition of Antigens

Cell-Mediated Immunity: Activation of T Lymphocytes and Elimination of IntracellularMicrobes

Humoral Immunity: Activation of B Lymphocytes and Elimination of ExtracellularMicrobes

Decline of Immune Responses and Immunological Memory

Hypersensitivity and Autoimmune Disorders

Mechanisms of Hypersensitivity Reactions

Immediate (Type I) Hypersensitivity

Antibody-Mediated (Type II) Hypersensitivity

Immune ComplexMediated (Type III)Hypersensitivity

T CellMediated (Type IV) Hypersensitivity

Autoimmune Diseases

Immunological Tolerance

Mechanisms of Autoimmunity: General Principles

General Features of Autoimmune Diseases

Systemic Lupus Erythematosus (SLE)

Spectrum of Autoantibodies in SLE

Etiology and Pathogenesis of SLE

Drug-Induced Lupus Erythematosus

Rheumatoid Arthritis

Sjgren Syndrome

Etiology and Pathogenesis

Systemic Sclerosis (Scleroderma)

Etiology and Pathogenesis

Inflammatory Myopathies

Mixed Connective Tissue Disease

Polyarteritis Nodosa and Other Vasculitides

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The immune system is vital for survival, because our environment is teeming with potentially deadly microbesand the immune system protects us from infectious pathogens. Predictably, immune deficiencies renderindividuals easy prey to infections. But the immune system is similar to the proverbial double-edged sword.

Although it normally defends us against infections, a hyperactive immune system may cause diseases thatcan sometimes be fatal. Examples of disorders caused by immune responses include allergic reactions andreactions against an individual's own tissues and cells (autoimmunity).

This chapter is devoted to diseases caused by too little immunity or too much immunologic reactivity. Wealso consider amyloidosis, a disease in which an abnormal protein, derived in some cases from fragments ofimmunoglobulins, is deposited in tissues. First, we review some of the important features of normal immuneresponses, to provide a foundation for understanding the abnormalities that give rise to immunological

diseases.

The Normal Immune Response

The normal immune response is best understood in the context of defense against infectious pathogens, theclassical definition of immunity. The mechanisms of protection against infections fall into two broadcategories. Innate immunity(also called natural, or native, immunity) refers to defense mechanisms that arepresent even before infection and that have evolved to specifically recognize microbes and protectindividuals against infections. Adaptive immunity(also called acquired, or specific, immunity) consists ofmechanisms that are stimulated by (adapt to) microbes and are capable of recognizing microbial andnonmicrobial substances. Innate immunity is the first line of defense, because it is always ready to preventand eradicate infections. Adaptive immunity develops later, after exposure to microbes, and is even more

Rejection of Tissue Transplants

Mechanisms of Recognition and Rejection of Allografts

Rejection of Kidney Grafts

Transplantation of Other Solid Organs

Transplantation of Hematopoietic Cells

Immunodeficiency SyndromesPrimary Immunodeficiencies

X-Linked Agammaglobulinemia (Bruton's Agammaglobulinemia)

Common Variable Immunodeficieny

Isolated IgA Deficiency

Hyper-IgM Syndrome

DiGeorge Syndrome (Thymic Hypoplasia)

Severe Combined Immunodeficiency

Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-AldrichSyndrome)

Genetic Deficiencies of the Complement System

Secondary Immunodeficiencies

Acquired Immunodeficiency Syndrome (AIDS)

Epidemiology

Etiology: The Properties of HIV

Pathogenesis of HIV Infection and AIDS

Natural History of HIV Infection

Clinical Features of AIDS

Amyloidosis

Properties of Amyloid Proteins

Pathogenesis of Amyloidosis

Classification of Amyloidosis


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powerful than innate immunity in combating infections. By convention, the term immune response refers toadaptive immunity.

INNATE IMMUNITY

The major components of innate immunity are epithelial barriers that block entry of microbes, phagocyticcells (mainly neutrophils and macrophages), dendritic cells, natural killer (NK) cells, and several plasmaproteins, including the proteins of the complement system. The two most important cellular reactions of

innate immunity are: inflammation, the process in which phagocytic leukocytes are recruited and activated tokill microbes, and anti-viral defense, mediated by dendritic cells and NK cells. Leukocytes and epithelial cellsthat participate in innate immunity are capable of recognizing components of microbes that are sharedamong related microbes and are often essential for the infectivity of these pathogens (and thus cannot bemutated to allow the microbes to evade the defense mechanisms). These microbial structures are calledpathogenassociated molecular patterns. Leukocytes also recognize molecules released by injured andnecrotic cells, which are sometimes called danger-associated molecular patterns. The cellular receptors thatrecognize these molecules are often called pattern recognition receptors. The best-defined patternrecognition receptors are a family of proteins called Toll-like receptors (TLRs)[1] that are homologous to theDrosophilaprotein Toll. Different TLRs are specific for components of different bacteria and viruses. TLRsare located on the cell surface and in endosomes, so they are able to recognize and initiate cellularresponses to extracellular and ingested microbes. Other microbial sensors are located in the cytoplasm,where they recognize bacteria and viruses that may have colonized cells. Upon recognition of microbes, theTLRs and other sensors signal by a common pathway that leads to the activation of transcription factors,

notably NF-B (nuclear factorB). NF-B turns on the production of cytokines and proteins that stimulate themicrobicidal activities of various cells, notably the phagocytes. Other cellular receptors bind microbes forphagocytosis; these include receptors for mannose residues, which are typical of microbial but not hostglycoproteins, and receptors for opsonins such as antibodies and complement proteins that coat microbes.

Epitheliaof the skin and gastrointestinal and respiratory tracts provide mechanical barriers to the entry ofmicrobes from the external environment. Epithelial cells also produce anti-microbial molecules such asdefensins, and lymphocytes located in the epithelia combat microbes at these sites. If microbes do breachepithelial boundaries, other defense mechanisms are called in.

Monocytesand neutrophilsare phagocytes in the blood that can rapidly be recruited to any site of infection;monocytes that enter the tissues and mature are called macrophages(Chapter 2). Dendritic cellsproducetype I interferons, anti-viral cytokines that inhibit viral infection and replication; these cells are describedbelow, in the context of antigen display to lymphocytes. Natural killer cellsprovide early protection against

many viruses and intracellular bacteria; their properties and functions are also described below.

The proteins of the complement system, which were described in Chapter 2, are some of the most importantplasma proteins of the innate immune system. Recall that in innate immunity the complement system isactivated by microbes using the alternative and lectin pathways; in adaptive immunity it is activated byantibodies using the classical pathway. Other circulating proteins of innate immunity are mannose-bindinglectin and C-reactive protein, both of which coat microbes for phagocytosis. Lung surfactant is also acomponent of innate immunity, providing protection against inhaled microbes.

The early innate immune response not only provides the initial defense against infections but is also involvedin triggering the subsequent, more powerful adaptive immune response.

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