Medical brain notes 30

  DISORDERS OF THE IMMUNE SYSTEM INTRODUCTION A fully functioning immune system is essential for maintaining health but, like all body systems, the immune system itself is subject to many clinical disorders. Immunological disease can occur for one of three reasons. Firstly,  immunodeficiency diseases  occur in individuals whose immune systems are inadequate, perhaps due to the absence or malfunction of essential components, making them susceptible to infectious disease and even to certain types of cancer. Secondly,  autoimmune diseases  can occur as a result of the immune system mounting an immune response against ‘self’ components. Finally,  immunological hypersensitivity  occurs when immune responses, often mounted against seemingly innocuous immunogens, result in tissue damage. Indeed, immunological hypersensitivities are among the commonest of immunological disorders.

  IMMUNODEFICIENCY DISEASES Immunodeficiency diseases result from a failure of one or more components of the immune system and may involve the absence or malfunction of organs, cells or proteins of the immune system. Where the immunodeficiency results from a direct defect within the immune system, the disease is classified as a  primary immunodeficiency (PID) . All PIDs are inherited or have a geneticcomponent. Most, but not all, primary deficiencies are congenital, that is are present from birth, although some do not manifest themselves until later in life.  Secondary immunodeficiencies (SIDs)  arise as a consequence of other conditions. For example, some viruses are associated with an immunosuppression, which may be transient, as for example in measles, or permanent, as in HIV infection. Conditions that can give rise to secondary immunodeficiency are listed in  Table 5.1 . Patients with immunodeficiency diseases invariably suffer infections more frequently and...

  PRIMARY IMMUNODEFICIENCY DISEASE Primary immunodeficiencies are classified according to the site of the immunological defect. The 100 or so inherited PIDs were classified into eight groups or tables ( Table 5.3 )  at a meeting of the International Union of Immunological Societies in 2003.

  Combined T and B deficiencies Deficiencies that affect both B and T lymphocyte numbers and/ or their functions are life threatening. Such deficiencies are termed   severecombined immunodeficiency (SCID) . The term SCID represents a groupof disorders associated with more than 20 different mutations and with a frequency of between one in 50 000 and one in 500 000 births. As some forms of SCID are inherited in an X-linked fashion , more boys than girls are affected, with the male : female ratio of approximately 3 : 1. Depending on the mutation involved, T and B cells may both be decreased (T – B –  SCID) or B cells numbers may be normal or increased (T – B + SCID). In the latter, the absence of T cells renders B cells functionally inactive, owing to the need for the cytokines produced by T H  cells for antibody production as described. In either case, the disorder becomes apparent in the first few weeks  or months of life with the mean age at diagnosis being 6.5 ...

  Antibody deficiencies The normal concentration ranges for the five immunoglobulin classes, IgM, IgG, IgA, IgE and IgD , in adults are shown in  Table 5.5 . Deficiencies involving immunoglobulins of all classes are commonly referred to as  agammaglobulinemias  or hypogammaglobulinemias , depending on the level of deficiency. However, with some disorders there may be a selective deficiency of a single immunoglobulin class, as in selective IgA deficiency, or a dysregulation, where some antibody classes are reduced while others are increased. During the first three months postpartum, the maternally derived IgG is catabolized and steadily disappears from the baby’s circulation. Between three and six months, serum IgG levels may be quite low, after which the levels begin to increase, and should normally attain ‘adult’ levels at about 12–18 months of age. In infants with transient hypogammaglobulinemia, the production of IgG is delayed considerably, sometimes for as long ...

  The DiGeorge anomaly and the Wiskott Aldridge syndrome The third group of PIDs ( Table 5.3 ) contains a number of well-defined immunodeficiency syndromes, of which the DiGeorge anomaly and the Wiskott Aldridge syndrome are well-known examples. The DiGeorge anomaly (DGA) is a developmental disorder involving organs that develop from the third and fourth pharyngeal pouches of the embryo. It is associated with a deletion or partial monosomy of chromosome 22 that results in a range of defects. Several different patterns of inheritancehave been reported, including autosomal dominant and autosomal recessive. Its incidence has been estimated to be between one in 20 000 to 66 000, depending on the country. The DGA is characterized by facial abnormalities, hypoparathyroidism and hypocalcemia with symptoms of convulsions and tetany, congenital heart disease that may be so severe as to be life threatening, and a small under-developed or sometimes absent thymus that results in a profound imm...

  The Chediak-Higashi syndrome Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder first described in 1943. It is sometimes classified as a phagocytic defect. However, even though phagocytic cells, such as neutrophils and monocytes, are defective, Natural Killer (NK) cells, which form the first line of defence against viruses, are also abnormal. The syndrome arises from a mutated form of the  CHS1  gene located on chromosome 1. The gene product is involved in the intracellular transport of proteins and the synthesis of storage granules in certain cells. The mutation results in neutrophils with abnormally large or ‘giant’ lysosomes and platelets with abnormal dense bodies. In addition, melanocytes, the pigment-producing cells of the skin, contain larger than normal melanosomes; the pigment storing organelles. Chediak-Higashi syndrome presents as an immune deficiency that leads to recurrent bacterial infections, most commonly with  Staphylococcus aure...

  Phagocytic defects Phagocytic cells, such as monocytes, macrophages and neutrophils, form part of the nonspecific immune defense. These cells kill ingested bacteria using several different mechanisms as described. A defect in any of these mechanisms can lead to increased incidences of infections. Thus, patients may be severely compromized by defective phagocytes, even if their B and T cell populations and functions are normal. Some examples of phagocytic defects are chronic granulomatous disease and leukocyte adhesion deficiency. Chronic granulomatous disease (CGD) is named from the granulomatous inflammatory nodules that present on the skin and in the gastrointestinal and genitourinary tracts. It is an inherited disorder of phagocytic cells characterized by their inability to generate the reactive oxygen intermediates needed to produce bactericidal compounds, such as hydrogen peroxide. The formation of reactive oxygen intermediates is dependent on NADPH oxidase activity. This en...

  Complement deficiencies The role of complement in immune defense was outlined. Here it will be described in more detail. The activation of complement results in the:   ·             lysis of bacteria;   ·             stimulation of the inflammatory response;   ·             promotion of phagocytosis;   ·             clearance of immune complexes.   The value of these roles cannot be overestimated. Complement may be activated by one of three pathways: the classical pathway, which is activated by IgG or IgM, following binding to an antigen; the alternative pathway, which is stimulated principally by components of the cell walls of bacteria and yeasts; and the lectin pathway, which is initiated by the binding of mannose binding lectin (MBL) t...

  AUTOIMMUNE DISORDERS The macromolecules of the body are potentially highly immunogenic but, fortunately, immune systems do not usually mount immune responses against them. In fact, we are ‘tolerant’ to ‘self’. Whatever mechanisms lie behind the induction and maintenance of tolerance, it is clear that a number of disorders arise when these mechanisms fail and the immune system starts to attack self antigens. Failures of immunological tolerance lie behind the development of  autoimmune disease . Autoimmune disease affects 5 to 7% of the population and autoimmune disorders are debilitating, chronic and painful. CLASSIFICATION OF AUTOIMMUNE DISORDERS Autoimmune disorders are often classified according to whether they are organ-specific, affecting only one organ or are systemic that is, affecting multiple organ systems ( Table 5.7 ). In addition, destruction of cells and tissues can be brought about by autoantibodies and/or cell-mediated immunity. For example, in multiple scleros...

  CLASSIFICATION OF AUTOIMMUNE DISORDERS Autoimmune disorders are often classified according to whether they are organ-specific, affecting only one organ or are systemic that is, affecting multiple organ systems ( Table 5.7 ). In addition, destruction of cells and tissues can be brought about by autoantibodies and/or cell-mediated immunity. For example, in multiple sclerosis (MS) patients produce antibodies against myelin, the fatty material surrounding the axons of nerves. In addition, MS patients have T H  and T C  lymphocytes in their blood and cerebrospinal fluid, which are specific for myelin protein. Thus, humoral and cell-mediated autoimmunity may contribute to the demyelination of nerves in MS patients. In some instances, autoantibodies can block or stimulate a cell receptor. Myasthenia gravis is an example of the former, while Graves disease is an example of the latter. Like most classification schemes, that of autoimmune disorders is not perfect. For example, Go...

  AUTOIMMUNE DISORDERS AFFECTING ENDOCRINE GLANDS Autoimmune disorders of the thyroid gland are among the most common autoimmune disorders. Some will be discussed. Autoimmune thyroiditis, also known as Hashimoto’s thyroiditis, results in hypothyroidism and myxedema. The disease presents, typically, in women of middle age who are overweight, lethargic, constantly feel cold, are constipated and have coarse, dry hair and skin. The thyroid is swollen with a generally painless goiter, but which has a rubbery consistency when palpated. A biopsy of the thyroid shows infiltration with both CD8+ and CD4+ T lymphocytes that progressively destroy the thyroid gland. Patients also have antibodies to thyroglobulin and to thyroid peroxidase, which can be determined by ELISA . Immunohistochemical techniques can show the patient’s serum to have antibodies that bind to microsomal antigens in sections of normal thyroid ( Figure 5.4 ). Patients may be given thyroxine to treat the myxedema, and thyroid...

  ANTIGLOMERULAR BASEMENT MEMBRANE DISEASE Antiglomerular basement membrane diseases are characterized by autoantibodies to the glomerular basement membrane (antiGBM). They include Goodpasture’s syndrome and Goodpasture’s disease. The former disorder shows glomerulonephritis, pulmonary hemorrhage and the presence of circulating antibodies to glomerular basement membrane; the latter is similar, but without the lung involvement. Both diseases are now included under the more general heading of antiGBM disease. Tissue damage is caused by antiGBM antibodies binding to the glomerular basement membrane and activating complement. Complement-mediated inflammation then ensues. The symptoms of glomerulonephritis include proteinuria and hematuria and erythrocyte casts ( Margin Note 5.3 ) are seen. The binding of antibodies to alveolar membranes causes  hemoptysis , that is, the coughing up of blood from the lungs and about 40% of patients experience chest pain. Hemorrhaging from the lungs...

  MYASTHENIA GRAVIS Myasthenia gravis (MG) is an autoimmune disorder in which patients produce antibodies to acetylcholine receptors at the neuromuscular junction of striated muscle. The antibodies block the receptors so that they fail to respond to acetylcholine ( Figure 5.6 ). This results in intermittent but progressive weakness of skeletal muscles, including those for breathing and the facial muscles involved in chewing, swallowing, talking and eye movements. The latter can lead to double vision and an inability to raise the eyelids, a condition known as  ptosis . Difficulty with respiration may lead to inadequate intake of air and an inability to clear secretions from the respiratory tract. The incidence of pneumonia is increased in these patients. Approximately 75% of patients with MG also have thymic abnormalities such as hyperplasia and thymoma. The incidence of MG has been quoted as up to 14 in 100 000, with a female to male ratio of about 3 : 2. The problems associat...