Prevalence and Impact

Chapter 8 This chapter outlines the different types of immune system alterations, specifically hypersensitivity reactions and deficiencies in immunity. Hypersensitivity reactions can be categorized by the immunologic mechanism causing the disease and the source of the antigen being attacked by the immune system. There are four main types of hypersensitivity reactions: type I (IgE-mediated reactions), type II (tissue-specific reactions), type III (immune complex-mediated reactions), and type IV (cell-mediated reactions). Prevalence and Impact Primary immune deficiency diseases are more common than cystic fibrosis, hemophilia, childhood leukemia, or many other well-known diseases Approximately 30 to 50 new cases per year in the United States from 2001 to 2007 354 inborn errors of immunity identified as of February 2017 Sex distribution is about even, although some specific diseases have a male or female predominance Commonly Diagnosed Deficiencies Common variable immune deficiency (34% of individuals with primary immune deficiencies) Selective IgA deficiency (24%) IgG subclass deficiency (17%) Classification and Groups Primary immune deficiencies recently reclassified into nine groups based on defective components of the immune or inflammatory systems Most common disorders are included within combined immunodeficiencies affecting both cellular and humoral immunity Other groups include predominantly antibody deficiencies, defects in phagocyte number or function, defects in innate immunity, and complement defects Examples of Primary Immune Deficiencies Severe combined immunodeficiencies (SCIDs): most severe disorders affecting the development of both T and B lymphocytes, low lymphocyte levels, absent or reduced immunoglobulin levels Bare lymphocyte syndrome: inability to produce MHC molecules, resulting in problems with antigen presentation and intercellular cooperation Wiskott-Aldrich syndrome (WAS): combined immune deficiency with a major defect in platelet function, characterized by low IgM antibody production and associated with bleeding, eczema, and recurrent infections DiGeorge syndrome: combined immunodeficiency with syndromic features caused by a 22q11.2 deletion, leading to multiple health issues including immune deficiencies DiGeorge Syndrome Lack or partial lack of the thymus leads to decreased T-cell numbers and function Defective development of the third and fourth pharyngeal pouches during embryonic development results in thymic defects and absence of the parathyroid gland Abnormal development of facial features, including low-set ears and fish-shaped mouth, are common in DiGeorge Syndrome Predominantly Antibody Deficiencies Result from defects in B-cell maturation or function Lower levels of circulating immunoglobulins (hypogammaglobulinemia) or absence of immunoglobulins (agammaglobulinemia) Selective IgA deficiency may occur, leading to recurrent infections and chronic intestinal candidiasis Bruton agammaglobulinemia (X-linked agammaglobulinemia) results in blocked development of mature B cells, leading to repeated bacterial infections Phagocyte Defects Range from inadequate numbers of phagocytes to defects in phagocyte function Chronic granulomatous disease (CGD) is a severe defect in the myeloperoxidasehydrogen peroxide system, resulting in recurrent severe pneumonias, granulomata, and infections Other phagocytic deficiencies include defects in leukocyte adhesion molecules and defects in the phagocytosis process or bacterial killing Defects in Innate Immunity Some immune deficiencies result in the inability to produce an immune response against a specific antigen In chronic mucocutaneous candidiasis, the interaction between Th17 lymphocytes and macrophages is ineffective, leading to recurrent Candida infections involving mucous membranes and skin Other defects in innate immunity include defects in Toll-like receptors and natural killer (NK) cells Primary defects in innate immunity can result in susceptibility to infections with mycobacteria, salmonella, and various viruses Complement Deficiencies Many complement deficiencies have been described C3 deficiency is a severe defect that leads to recurrent life-threatening infections with encapsulated bacteria at an early age Deficiencies of terminal components of the complement cascade are associated with increased infections with Neisseria species Mannose-binding lectin (MBL) deficiency and defects in the alternative pathway of complement activation increase the risk of infection with specific microorganisms, such as Saccharomyces cerevisiae, N. meningitidis, and S. pneumoniae Other complement deficiencies involve defects in various complement components and receptors Evaluation and Care of Primary Immune Deficiencies Complete blood count (CBC) with a differential is a basic screening test Quantitative determination of immunoglobulins (IgG, IgM, IgA) and total complement (CH50) can help identify antibody production and complement defects Replacement Therapies for Primary Immune Deficiencies IVIG (intravenous immunoglobulin) is often used to treat B-cell deficiencies causing hypogammaglobulinemia or agammaglobulinemia Gene therapy shows promise in providing long-term replacement of specific immune factors Stem cell transplantation can be used to treat defects in lymphoid cell development or thymic defects Primary Immune Deficiencies Some primary immune deficiencies (e.g., SCID, DiGeorge syndrome, chronic mucocutaneous candidiasis) can be treated with transplantation or thymic epithelial cells Enzymatic defects causing SCID can be treated successfully with transfusions of glycerol frozen-packed erythrocytes Bone marrow transplants are routinely used to treat SCID, but can lead to graft-versushost disease (GVHD) GVHD can be diminished by removing mature T cells from tissue used for treatment Mesenchymal stem cells (MSCs) may be useful in treating GVHD Secondary Immune Deficiencies Secondary immune deficiencies are more common than primary deficiencies They are complications of other conditions such as pregnancy, aging, infections, malignancies, physical trauma, medical treatments, other diseases, and genetic syndromes Many secondary deficiencies are not clinically relevant or only have a minor impact on immune function Some secondary immune deficiencies, such as malignancies and immunosuppressive treatments, can be severe and result in recurrent life-threatening infections