Basal membranes

Idiopathic Addison's disease

Atrophic gastritis, pernicious anemia

Graves' disease

Myasthenia gravis pseudoparalytica

Diabetes mellitus

Hashimoto's thyroiditis


Pulmonary bleeding Goodpasture's syndrome

Immune Defects

Immune defects express themselves through frequent, prolonged, and often life-threatening infections (also caused by otherwise harmless infectious agents) and through certain tumors.

Among defects of nonspecific defense are those of the complement system (infection with extracellular pathogens, e.g., the Neisseria), of the NK cells (infection with intracellular pathogens, e.g., listeria or herpes virus) as well as of mannose-binding proteins ([MBP] ^ p. 44). Disorders of phagocytosis can concern the cell number (e.g., leukopenia due to G-CSF deficiency; agranulocytosis due to radiotherapy or chemotherapeutic agents), or may be functional. In leukocyte adhesion defect (LAD), a defect of the integrin subunit (CD18) prevents margination; in lazy leukocyte syn-^ drome, migration is slowed down; in chronic oo (or septic) granulomatosis oxidants are not 2 formed; and in Chediak-Higashi syndrome the rn fusion of phagosomes with lysosomes is abnormal.

Humoral immune defects can be caused by disorders of maturation, function, or activation of B cells. Without antibodies the organism is powerless, especially against pus-forming pathogens, because their polysaccharide membrane cannot be phagocytized without opson-ification. Examples are 1) selective IgA deficiency (very common, with an incidence of 1 in 700), in which a lack of mucosal protection frequently leads to respiratory and gastrointestinal infections and to an increased incidence of susceptibility to allergies; 2) congenital agammaglobulinemia, in which a (X-linked) defect of Bruton-type tyrosine kinase hinders the maturation of B cells; 3) hyper-IgM syndrome, in which IgM concentration is greatly increased, but that of IgG and IgA is reduced (no class jump due to defect of CD40 ligands; ^ p.47, B4); and 4) so-called variable immune defect (deficient stimulation of B cells by CD4-Tcells).

Disturbances of cellular immune defense occur in thymus aplasia (DiGeorge's syndrome) and in combination with humoral immune defects. They extend from abnormal stem cell differentiation (reticular dysgenesis) via defec-58 tive HLA formation (naked lymphocytes syndrome) to the life-threatening combined B-

cell and T-cell disorder (severe combined immunodeficiency disease [SCID], e.g., due to a deficiency of adenosine deaminase or purine nucleoside phosphorylase).

AIDS (acquired immunodeficiency syndrome) is caused by HIV-1 or HIV-2 (HIV = human immunodeficiency virus) (^A). The genome of these retroviruses is coded in two almost identical molecules of a single-strand RNA (ssRNA). Built into the virion (complete virus particle) cover is the gp120-protein (^ A1) that docks simultaneously on CD4 and on a chemokine receptor (= CCR5 at the beginning of an infection; = CXCR4 at the final stage) of the host cell membrane, thus eliciting membrane fusion and virion endocytosis (^A2). (People with a CCR5 defect are largely protected against an HIV infection). In addition to CD8 cells, it is mainly the CD4-TH cells that are affected. In the latter, ssRNA is transcribed to cDNA by a virion-endogenous reverse tran-scriptase, finally being incorporated as a double-strand dsDNA (provirus) into the host cell's genome (latent stage). Activation of the CD4 cells (at the onset of infection and the late stage) triggers expression of the provirus. The proteins that result from this, tat and rev as well as Nficb from the host cell, take part in the formation of new virions that are exocy-tozed (viremia; ^A3,4). The CD4 cell may be destroyed during these stages (see photograph), particularly as it is attacked by its own immune defenses (anti-gp120-IgG + complement; viral peptide recognition by cytotoxic T cells). Noninfected CD4 cells may also die (HLA-independent apoptosis) so that in the late stage a serious CD4 cell deficiency develops (^ A4). The changes in cytokine concentration (^ A5) decimate TH1 cells and cytotoxic T cells. The body is now ever more helplessly exposed to other, normally harmless, pathogens (e.g., fungi) and certain tumor cells (Kaposi's sarcoma, lymphoma) (<500CD4 cells/|L blood: ARC [= AIDS-related complex]; <200: fullblown AIDS). Many years can pass from the initial viremia (high p24-antigen level with IgM formation) and the ARC with renewed viremia (no more IgM) (^ A4), during which the proviruses survive in relatively few (106), inactive CD4 cells (mostly in lymph nodes).

CD4-T cell death

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