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© Dirk Biddle
The causes and risk factors associated with many vasculitis conditions are often unknown, thus the term idiopathic, meaning of unknown cause, is often utilised. It has been speculated however that a viral, bacterial, or even fungal infection may trigger an inflammatory immune response that somehow becomes self-sustaining. It has further been speculated that vasculitides affecting children (eg; Kawasaki disease) predominantly (and only) do so because adults have built an effective immune response to an as yet undiscovered viral or bacterial cause. What does seem clear however is that many vasculitides are associated with some form of autoimmune response.
The most commonly incriminated factor in the inflammatory immune response underlying vasculitis conditions is the deposition of immune complexes. Immune complexes are antibody/antigen complexes that in circulation attract neutrophils, a type of white blood cell (leucocyte), to destroy the antigen. If these immune complexes deposit on vascular walls they can cause reactive inflammation and damage within the vessel wall.
In autoimmune forms of vasculitis a cell-mediated pathological mechanism may be involved. This type of inflammatory immune response more directly involves the infiltration of lymphocytes (T-cells, B-cells, and Natural killer cells) and neutrophils into the vessel walls. The details of these interactions will be elucidated in coming sections.
More generally however, viral hepatitis (B & C) is a regularly recognized cause of vasculitis (eg; some cases of Cryoglobulinemia and Polyarteritis nodosa) and human immunodeficiency virus (HIV) has been associated with some cases of CNS vasculitis and Cutaneous leukocytoclastic angiitis. Giant cell arteritis may represent an immune response toward a viral antigen present in the arterial wall (particularly reinfection with parainfluenza virus) (8). Foreign proteins such as streptokinase , those found in vaccines, and those used in monoclonal antibody therapy have been associated with, for example, serum sickness syndrome and with Cutaneous leukocytoclastic angiitis (8). There have been reports of Mycobacterium tuberculosis in association with Takayasu's arteritis, however these have almost always been in populations where M. tuberculosis has high endemicity (8). Wegener's granulomatosis has been associated with higher rates of chronic nasal carriage of Streptococcus aureus (8). Kawasaki disease has been linked to several infectious agents, such as streptococci, staphylococci, Epstein-Barr virus, retrovirus and parvovirus B19 (8). Henoch-Schönlein purpura has also been linked to several pathogens, most commonly group A beta-hemolytic streptococcus (8). However, it must be remembered that these associations are noted only in a certain percentage of cases of the particular vasculitides mentioned and that the majority of instances of the same vasculitis conditions remain idiopathic in nature.
Interestingly, cyclical and seasonal variations in symptom presentation may also point to bacterial or viral causes. Cyclical occurrences of Giant cell arteritis in Olmsted County (USA), peaking every seven years, and peak incidences of Giant cell arteritis in Denmark associated with Mycoplasma pneumoniae may point to infectious aetiology (9). A cyclical trend has also been noted in ANCA associated glomerulonephritis and systemic vasculitis (10) and seasonal variations have further been noted in Wegener’s granulomatosis, with the highest rate of onset in winter (9). Seasonal links have also been noted in other systemic vasculitides such as Polyarteritis nodosa (11).
Fungi have also been implicated and those such as mucor, aspegillus and actinomyces are noted to have a specific tendency to invade vessel walls and produce infarction and haemorrhages (12).
The most common drugs that can cause vasculitis include a group of antibiotics known as sulphonamides (particularly beta-lactam drugs), penicillins, nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics (13). However, almost all drugs are potential causes, with cocaine, amphetamines and even over-the-counter cold preparations implicated. Affected individuals of drug induced (and therefore secondary) vasculitis conditions may present with serological and pathological parameters identical to idiopathic forms of vasculitis, however the withdrawal of the offending agent is often sufficient to induce a prompt resolution of clinical manifestations.
Foods or food additives may even cause vasculitis (14, 15) and a direct link with tobacco products has been drawn in relation to Buerger’s disease (16).
Malignancy, such as lymphomas, leukaemia , myeloproliferative , and myelodysplastic syndromes may be also associated with secondary vasculitides. Solid tumours are less commonly associated but effective tumour therapy has led to an apparent cure of the secondary vasculitis in some patients (17). Indeed this feature has been noted in a number of secondary vasculitides where effective treatment of the primary disease process may remit the severity of, or even affect a cure of, the secondary vasculitis. Alternatively there are cases where the medications used to treat the primary disease are believed to have caused the secondary vasculitis. However, ascertaining whether the drug or the infection is responsible for a secondary vasculitis is often impossible because the occurrence of the vasculitis postdates both the underlying infection and the medication used to treat that infection.
Collagen related vascular diseases account for 10-15% of vasculitis cases and in particular, Rheumatoid arthritis , Sjögren syndrome , and Systemic lupus erythematosus have associated vasculitis conditions (18). Often too, the presence of vasculitis denotes an active underlying disease process and poorer prognosis.
Genetic influences on the vasculitides remain largely unknown, however, the presence of particular genes have been implicated as a risk factor (but generally not as a causal factor) for some vasculitis conditions. Population, family and twin studies have shown that genetic factors exert a significant influence on susceptibility to autoimmune diseases of which Rheumatoid arthritis, Systemic lupus erythematosus and Sjögren syndrome are typical examples (19). The acute onset of many of the primary vasculitides is often associated with a specific age group (mid-life being a common age of onset) and gender and race may also play a role in susceptibility to specific types of vasculitis conditions.
Specific genetic markers and associated genes are discussed in detail later in this article.
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a) Autoimmune Diseases Are illnesses which occur when the body tissues are attacked by its own immune system. The immune system is a complex organisation within the body that is designed normally to seek and destroy invaders of the body, particularly infections. Patients with these diseases have unusual antibodies in their blood that target their own body tissues. (OMD)"
b) Immune Complexes:Multimolecular antibody antigen complexes that may be soluble or insoluble depending upon their size and whether or not complement is present. Immune complexes can be filtered from plasma in the kidney and the deposition of the complexes gives rise to glomerulonephritis probably because of the trapping of neutrophils via their Fc receptors. (OMD)"
c)Antibody:Any of a large number of proteins of high molecular weight that are produced normally by specialized B-cells after stimulation by an antigen and act specifically against the antigen in an immune response, that are produced abnormally by some cancer cells, and that typically consist of four subunits including two heavy chains and two light chains - called also immunoglobulin. (M+) Antigen: A (usually) protein or carbohydrate substance (as a toxin or enzyme) capable of stimulating an immune response. (M+)"
d) Neutrophil:A granulocyte that is the chief phagocytic white blood cell."
e) Leukocyte:= White Blood Cell(WBC) a cell which circulates in the blood and lymphatic system and harbours in the lymph glands and spleen. They are part of the immune system responsible for both directly (T-cells and macrophages) and indirectly (B-cells producing antibodies) attacking foreign invaders of the body. They are colourless, lack haemoglobin, contain a nucleus, and include the lymphocytes, monocytes, neutrophils, eosinophils, and basophils. (OMD)"
f) Pathological:Of or pertaining to pathology. (OMD) Altered or caused by disease. (M+) Pathology: The branch of medicine concerned with the study of the essential nature of disease, especially its structural and functional effects on the body and the anatomic and physiological deviations from normal that constitute or characterize a particular disease."
g) T-cells:Any of several lymphocytes (as in helper T-cell) that differentiate in the thymus, possess highly specific cell-surface antigen receptors, and include some that control the initiation or suppression of cell-mediated and humoral immunity (such as by the regulation of T- and B-cell maturation and proliferation) and others that lyse antigen-bearing cells - called also T-lymphocyte. (M+)"
h) B-Cells:A type of lymphocyte normally involved in the production of antibodies to combat infection. It is a precursor to a plasma cell. During infections, individual B-cell clones multiply and are transformed into plasma cells, which produce large amounts of antibodies against a particular antigen on a foreign microbe. This transformation occurs through interaction with the appropriate CD4 T helper cells. (OMD)"
i) Natural Killer Cells:Large granular lymphocytes which do not express markers of either T or B-cell lineage. These cells do possess Fc receptors for IgG and can kill target cells using antibody-dependent cell-mediated cytotoxicity. NK cells can also use perforin to kill cells in the absence of antibody. Killing may occur without previous sensitization. (OMD)"
j) Antigen:A (usually) protein or carbohydrate substance (as a toxin or enzyme) capable of stimulating an immune response. (M+)"
k) Streptokinase:Plasminogen activator released by Streptococcus pyogenes. Occurs in two forms, A and B. (OMD) A proteolytic enzyme from haemolytic streptococci active in promoting dissolution of blood clots. (M+)"
l) Monoclonal:Produced by, being, or composed of cells derived from a single cell (a monoclonal tumou) ; especially - relating to or being an antibody derived from a single cell in large quantities for use against a specific antigen (as a cancer cell). (M+) Thus Monoclonal antibody therapy."
m) Serum Sickness:A hypersensitivity response (type III) to the injection of large amounts of antigen, as might happen when large amounts of antiserum are given in a passive immunisation. The effects are caused by the presence of soluble immune complexes in the tissues. (OMD)"
n) Aetiology:A branch of knowledge concerned with the causes of particular phenomena, specifically a branch of medical science concerned with the causes and origins of diseases. The study of factors of causation or those associated with the causation of disease or abnormal body states. (OMD)"
o) ANCA:(Anti-Neutrophilic Cytoplasmic Antibody). Anti-neutrophilic cytoplasmic antibodies are used as diagnostic markers for systemic vasculitis."
p) Beta-Lactam:A class of broad spectrum antibiotics that are structurally and pharmacologically related to the penicillins and cephalosporins. (OMD)"
q) Diuretic:Agents that promote the excretion of urine through their effects on kidney function. (OMD)"
r) Lymphoma:A (usually) malignant tumour of lymphoid tissue. (M+)"
s) Leukaemia:An acute or chronic disease of unknown cause in man and other warm blooded animals that involves the blood forming organs, is characterised by an abnormal increase in the number of leucocytes in the tissues of the body with or without a corresponding increase of those in the circulating blood and is classified according of the type of leucocyte most prominently involved. (OMD)"
t) Myeloproliferative:Pertaining to or characterised by unusual proliferation of myelopoietic tissue. (OMD)"
u) Myelodysplastic Syndrome:A group of disorders characterised by low white blood cell counts, low platelet counts, and, in some cases, increased monocytes. The primary problem is in the bone marrow cellularity. (OMD)"
v) Rheumatoid Arthritis:Chronic inflammatory disease in which there is destruction of joints. Considered by some to be an autoimmune disorder in which immune complexes are formed in joints and excite an inflammatory response (complex mediated hypersensitivity). Cell-mediated (type IV) hypersensitivity also occurs and macrophages accumulate. This in turn leads to the destruction of the synovial lining (see pannus). (OMD)"
w) Sjögren Syndrome:An immunologic disorder characterised by progressive destruction of the exocrine glands (sweat glands, lacrimal glands, salivary glands). Symptoms include dry eyes, dry mouth, persistent cough (dry airways) and lack of saliva. Approximately 30% also have rheumatoid arthritis. Kidney involvement (kidney dysfunction) is seen in 40% of patients. Affects predominately females in their thirties to forties. The lungs, peripheral nerves, blood vessels (vasculitis) and thyroid may also be affected. (OMD) Treatment to overcome dry eyes and mouth are commonly available and depending on the nature and severity of symptoms, other medications are available, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and immunosuppressive drugs."
x) Systemic Lupus Erythematosus: A disease, probably autoimmune with antinuclear and other antibodies in plasma. Immune complex deposition in the glomerular capillaries is a particular problem."
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8. Mohan N., Kerr G. (2003) Infectious Etiology of Vasculitis: Diagnosis and Management. Current Rheumatology Reports, 5, 136-141.
9. Scott D., Watts R. (2000) Systemic vasculitis: epidemiology, classification and environmental factors. Annals of the Rheumatic Diseases, 59, 161-163.
10. Tidman M., Olander R., Svalender C., Danielsson D. (1998) Patients hospitalised because of small vessel vasculitis with renal involvement in the period 1975-95: organ involvement, anti-neutrophil cytoplasmic antibodies patterns, seasonal attack rates and fluctuation of annual frequencies. Journal of Internal Medicine, 133-41.
11. Raynauld J., Bloch D., Fries J. (1993) Seasonal variation in the onset of Wegener's granulomatosis, polyarteritis nodosa and giant cell arteritis. Journal of Rheumatology, 20, 1524-1526.
12.http://www.medcyclopaedia.com/library/topics/volume_vi_1/v/VASCULITIS_INTRACRANIAL.aspx
13.http://www.online-ambulance.com/articles/doc/2/grp/Dermatology/pg/1/art/Drug_erruptions.htm
14.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=1676224&dopt=Abstract
15. Businco L, Falconieri P, Bellioni-Businco B, Bahna S. (2002) Severe food-induced vasculitis in two children. Pediatric Allergy Immunology, 13, 68.
16. Szuba A, Cooke J. (1998) Thromboangiitis obliterans. An update on Buerger's disease. Western Journal of Medicine, 168(4), 255-260.
17. Kelley N. (1997) Vasculitis and related disorders. In: Textbook of rheumatology. 5th ed. Philadelphia: Saunders 1079-1101.