Diseases of Immunity III study notes Polyarteritis Nodosa - a serious disease characterized by focal, three-layer, necrotizing inflammation, with deposition of immune complexes and complement, involving medium-sized and small arteries in many different organs; resembles classic type III injury - damage to the vessel walls results in thrombosis and infarction - most common site of involvement is the kidney - destruction of collagen and elastin in hte walls of the damaged vessels causes the nodose ballooning - death results from stroke, high blood pressure, kidney failure, or massive bleeding from GI infarcts - usually goes neglected for weeks - does not involve the lungs - best place to biopsy is probably a tender muscle or testis - important to make the diagnosis, because this deadly disease responds very well to treatment Wegener's Granulomatosis - a multi-system vasculitis which appears to involve both type III and IV immune injury; think disease is caused by antibodies against proteinase 3; apparently the same as myeloblastin, a neutrophil component and differentiation factor - characterized by acute necrosis and inflammation of short portions of the walls of vessels, primarily involving the respiratory tract, kidneys, and spleen - there are also extravascular, necrotizing granulomas in the respiratory tree, especially the nasal sinuses and lung parenchyma - patients commonly die from exsanguinating pulmonary hemmorhage - most show severe damage to renal glomeruli - most patients have involvement of eyes, and problems with their ears - several cases with skin involvement have been mistaken for pustular acne - the antiproteinase 3 antibody shows in almost all cases - neutrophils and endothelial cells express proteinase 3 on the surfaces; (some macrophages have proteinase 3, accounting for the granulomas) - diagnose using mnemonic ELK : ent-lungs-kidney - treatable using cyclophosphamide - diagnoses usually accomplished using open lung biopsy Amyloidosis -amyloid is a class of insoluble, homogenous, eosinophilic substances that accumulate in the extracellular spaces; their common link is B-pleated sheets, and therefore cannot be effetively handled by the body - enough amyloid makes an organ rubbery and waxy and sometimes useless - cells undergo pressure atrophy - amyloidosis is a group of curious systemic and localized diseases with varied and bizarre clinical presentations - Alzheimer's disease regularly includes amyloid B/A4 deposition in the brain and its vessels - new name is B-fibrillosis - most amyloids are altered forms of various proteins that exist in the healthy body - exhibit in the Congo Red dye - 90% of amyloid is non-branching fibrils, 10% P-component - P-component is pentamers of glycosylated alpha-1 globulin, an acute phase protein related to C-reactive protein which is produced by the liver in response to IL-1 production by macrophages; these pentamers bind to any form of amyloid - amyloidosis often goes unrecognized - isolated cardiac amyloidosis is the problem in an unknown number of elderly patients with heart disease, especially heart block due to old age - amyloids are classified by the protein by which they are derived - amyloids derived from immunoglobulin light chains - likely to involve many different organs; the amyloid is composed of some or all of the lambda or kappa light chains of immunoglobulin molecules; light chain deriver is called amyloid AL or amyloid B; most patients have evidence of a hyperactive clone of B cells - most patients have overt plasma-cell myeloma producing light chains, or related diseases such as B cell lymphomas - even more patients have benign monoconal gammopathy Amyloidosis derived from SAA protein (amyloid A) - the amyloid is composed of a portion of serum amyloid associated protein - the liver increases SAA production by several orders of magnitude during the acute phase reaction in response to IL-1 from macrophages - most patients with classic "secondary" amyloidosis have this type of amyloid - important causes of reactive systemic amyloidosis are longstanding TB, leprosy, syphilis, osteomyelitis, bronchectasis, CF survivors - familial Mediterranean fever - autosomal recessive disease with recurring serositis - lupus patients rarely get amyloidosis Amyloid derived from transthyretin - B-pleated transthyretin appears in many elderly people - seldom significant except within the heart, where it accounts for an unknown number of cases of unexplained heart block, other arrhythmias, and sudden death - massive depositions of senile amyloid interfere with ventricular function, but just a little can disrupt the conduction system - amyloid C also occurs in other clinical settings - most familial amyloidosis syndromes - polyneuropathy is the principal feature of this type of amyloidosis (autosomal dominant disease) Amyloidosis derived from a hormone polypeptide - occasionally such material fills the stroma of tumors of the corresponding endocrine organ - carcinoma of the C-cells of the thyroid has a stroma rich in B-pleated precalcitonin Amyloidosis composed of B-2-microglobulin (amyloid H) - amyloid arthropathy is a problem in kidney-failure patients who have been on hemodialysis for years - B-2-microglobulin is the light chains of HLA antigens; it is increased in serum of chronic renal failure, and it is the B-pleated substance in cases of dialysis-related amyloid arthropathy which have been studied - does not seem to regress when the hemodialysis is replaced by transplanted kidneys Amyloid composed of amyloid A4 protein - amyloid in senile plaques, neurofibrillary triangles, and cerebral vessels of Alzheimer's and Down's syndrome; not the main problem in Alzheimer's Amyloid composed of infectious prions (PrP) - the amyloid within the brain in Creutzfeldt-Jakob disease; prions are not viruses Organ involvement in systemic amyloidosis syndromes - kidney - gets deposited in the glomeruli, the blood vessels, and around the tubules; usually the glomerular basement membrane becomes too leaky to proteins, and the patient gets the nephrotic syndrome; renal involvement is a major cause of death - heart and vessels - amyloidosis C is limited to the heart; in any form of systemic amyloidosis, involvement of the heart may be severe to mild; depositions begin in the subendocardium; in minor cases, tiny deposits on the arterial endocardium - the heart in severe cardiac amyloidosis is stiff and heavy; half of the patients amyloidosis B have pump failure or dangerous rhythm disturbances - the vessel walls everywhere are often heavily involved, though infarct is unusual - GI tract - stiff tongue is a well known problem in both systemic (B) and localized amyloidosis - malabsorption - deposits in ganglia and wall of the gut makes normal peristalsis impossible - liver - deposited first in perisinusoidal spaces, and this appears to crunch the hepatocytes after a while - liver seldom fails - adrenal gland - can present adrenal cortical insufficiency - bleeding tendency - amyloid deposited around small blood vessles seems to render them more fragile - similar to scurvy - spleen - usual in systemic amyloidosis - most patients have increased circulating platelets, but the relative loss of splenic function is among the least of these peoples problems - a sago spleen has its amyloid in hte white pulp - a lardaceous spleen has its amyloid in the red pulp - skin - may be invlved trivially - nerves - some weakness and loss of sensation is common in amyloidosis, with or without unpleasant sensation - wrist - carpal tunnel syndrome developing in an older person makes the astute clinician suspect amyloidosis - lungs - two patterns occur - nodules (asymptomatic) or diffuse interstitial infiltration (dyspnea) Diagnosis - biopsy of solid tissue with amyloid in it - be suspicious of older patients - gingival or rectal tissue - aspiration of subcutaneous fat is a way to start looking for amyloid Treatment and prognosis - no satisfactory treatment - pts with amyloid B die in one year from heart problems - pts with amyloid A die in around ten years from kidney failure - cancer chemotherapy can slow progression of amyloid B - treat underlying disease of amyloid A - congophilic angiopathy will result in intracranial bleeding regardless of any treatment Immunodeficiency - systemic dieases which result in immunodeficiency include alcoholism, diabetes, nephrotic syndrome, uremia, and Cushing's syndrome; also malnutrition - patients with primary deficits in cell-mediated immunity almost all have oral candidiasis; patients with primary deficits in the antibody-complement phagocytotic system have problems with pyogenc bacteria Hereditary Immunodeficiencies - X-linked hypogammaglobulinemias - B cells are absent, fail to mature, or at least fail to respond to infection; lymph nodes are tiny, without germinal centers; deficiency in Burton's B-cell progenitor tyrosine kinase - all classes of IG are absent; when mother's Ig are gone, sever pyogenic bacterial infections begin - the disease in controlled with injection of gamma globulin - Isolated IgA deficiency - 1 in 300 people - serum secretory IgA is low or absent - most serious hazzard is iatrogenic anaphylaxis from the second administration of blood plasma - DiGeorge's syndrome - the third and fourth branchial pouches fail to form - while the patient is being treated for tetany and cardiac malformations just after birth, the lack of T-cells becomes evident as a fungal, viral, or other infection - Severe combined immunodeficiency (SCID) syndromes - a variety of profound deficiencies of both T-cell and B-cell function - Swiss type lymphogenic agammaglobulinemia is several autosomal recessive disorders - perhaps half of autosomal-recessive SCID are due to adenosine deaminase deficiency or another defect in purine salvage; problem is that too much adenosine builds up, and gets turned into dATP, which is very poisonous for all lymphocytes - ADA deficiency was the first disease to be cured by introduction of the normal gene into cells - at least three X-linked combined immunodeficency are known - one form of SCID, the IL-2 receptor is defective - another of the X-linked dieases affect David the bubble boy - Ataxia-telangiectasia - a poorly understood autosomal-recvessive systemic problem involving brain, vessels, and the immune system - AT heterozygotes have poor tolerance for radiation therapy; increase in cancer risk - cellular immunity against viruses is poor, and many of these patients cannot make IgA or IgE; patients die form lung infection or cancer - Wiskott-Aldrich syndrome - deficeincy of CD43, found on all human leukocytes; X-linked recessive trait - affected boys have eczema, low platelet counts and volumes, and repeated infections associated with variable losses of cellular immunity and/or hypercatabolism of immunoglobulin - prognosis is poor unless successful bone transplant - splenectomy can add a few years - moderate increase in lymphomas, perhaps due to hyperplasia of the lymphocytes - X-linked immunodeficiency - patients are unable to rid themselves of Epstein-Barr virus Common variable immunodeficiency - an unclassifiable group of syndromes that can begin in anyone at any age, but mostly in young adults; patients suffer from recurrent bacterial infections - B cells are present in normal numbers, but fail to turn into plasma cells as they should - often there is tremendous hyperplasia of the useless germinal centers, simulating nodular malignant lymphoma Genetic deficiencies of the complement system - hereditary agioedema - (C1 esterase inhibitor deficiency) - an autosomal dominant deficiency of an inhibitor of the early phase of classical complement activation - patient suffers dramatic edema in various parts of the body following minor insults - angioedema of the larynx occasionally causes sudden death in these patients - complement component deficiency syndromes - increased risk for infection and/or sytemic lupus-like illness - C2 deficiency presents an anti-nDNA-negative lupus-like picture