Inflammatory diseases of unknown etiology

Research into inflammatory diseases of unknown etiology often starts with a study of the inflammation process to see if it provides any clues to the etiology of the disease. In general, there are two basic types of inflammation, acute and chronic. In acute inflammation the predominant cells involved are neutrophils. In chronic inflammation, the predominate cells involved are mononuclear cells, such as monocytes, macrophages, lymphocytes, and plasma cells.

Historically, many inflammatory diseases of unknown etiology have turned out to be caused by autoimmunity, genetic predispostion, allergy, neurodegeneration, or infection.^[1] A well known example being gastric and duodenal ulcers, which were demonstrated to often be caused by a bacteria, Helicobacter pylori. Dr. Barry Marshall won the Lasker Prize in Medicine in 1995,[1] and along with Dr. Robert Warren won the Nobel Prize in Medicine in 2005.[2].

Regarding the theory of infectious causes of inflammatory diseases, one study in 1998 speculated that:

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Alzheimer's Disease

One review articles states, "Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation." (PMID 10858586)

Adult-onset Still's disease

One article reports, "Adult-onset Still's disease is a rare systemic inflammatory disease of unknown etiology, characterized by daily high, spiking fevers, evanescent rash, and arthritis."^[3]

Acute retinal pigment epitheliitis

Acute retinal pigment eptheliitis is one cause of sudden visual loss, often occurring in middle-aged men, but often with spontaneous recovery. The pathology is inflammation of the retinal pigment epithelium. It can occur in younger patients, sometimes associated with a viral illness.^[4] However, in most cases acute retinal pigment epitheliitis is an inflammatory disease of unknown etiology.

Tietze's Syndrome

Tietze's Syndrome is an inflammatory disease of the chest. According to once review article, "The disease has been characterized as a tender, non-suppurative swelling in the upper costosternal region. The etiology and pathology of the disease are still unknown."^[5]

Atherosclerosis

Atherosclerosis is inflammation of the blood vessels, or "hardening of the arteries." This clogging of the arteries is largely blamed on cholesterol. Several studies, however, suggest that a microbe or microbes may play a role in atherosclerosis. One review article says, "Immunoinflammatory processes due to chronic infection are thought to be one of the definitive atherogenetic processes."^[6] One review article says, "Atherosclerosis is no longer considered a disorder of lipid accumulation, but a disease process characterized by the dynamic interaction between endothelial dysfunction, subendothelial inflammation and the 'wound healing response' of the vascular smooth muscle cells." The same article, however, goes on to say that, "However, despite compelling experimental evidence, clinical studies looking at the role of infection in atherogenesis have lacked consistency.^[7] So, despite several microbes being implicated, atherosclerosis can still be considered an inflammatory disease of unknown etiology. Chlamydia pneumonia is one of the organisms being considered as a cause of atherosclerosis. One review study says, "C pneumoniae infection is strongly associated with coronary artery disease, as well as with atherosclerosis of the carotid artery, aorta, and peripheral arteries. This association has been shown in seroepidemiologic studies and by direct detection of the organism in atherosclerotic lesions by immunohistochemistry, polymerase chain reaction, electron microscopy, and tissue culture."^[8] Nanobacteria have also been found in atherosclerosis, but the finding must be interpreted with caution, as one study says, "Identification of nanobacteria-like particles at the lesion supports, but does not by itself prove the hypothesis that these agents contribute to the pathogenesis of atherosclerosis, especially vascular calcifications."^[9]

Behçet's Disease

Behcet's disease is an inflammatory disease of blood vessels. "The exact cause is unknown. It is believed that an autoimmune reaction may cause blood vessels to become inflamed, but it is not clear what triggers this reaction."^[10]

The White Dot Syndromes

The "White Dot Syndromes" are described in one review article as "a group of idiopathic multifocal inflammatory conditions involving the retina and the choroid. They are characterized by the appearance of white dots in the fundus."^[11]

Forms include:

• acute posterior multifocal placoid pigment epitheliopathy
• serpiginous choroiditis,
• birdshot chorioretinopathy,
• multifocal choroiditis with panuveitis,
• diffuse subretinal fibrosis syndrome,
• punctate inner choroidopathy,
• multiple evanescent white dot syndrome, and
• diffuse unilateral subacute neuroretinitis

The etiology of these inflammatory diseases is mostly unclear, however, "Some of these conditions share an association with systemic infectious diseases. In addition, treatment of these diseases is similar."^[12]

Granuloma annulare

Granuloma annulare is an inflammatory disease of the skin, but the cause remains unclear.^[13]

Rheumatoid arthritis

Rheumatoid arthritis is an inflammatory disease of unclear etiology.^[14] As one review article says, "Rheumatoid arthritis (RA) is represents the most common chronic inflammatory joint disease and is still a major medical challenge because of unsolved issues related to the etiologic and pathogenetic questions."^[15]

Sjögren's Syndrome

According to the Merk Manuel, "Sjögren's syndrome is characterized by excessive dryness of the eyes, mouth, and other mucous membranes. Sjögren's syndrome is thought to be an autoimmune disorder, but its cause is not known. It is more common in women than in men. White blood cells infiltrate the glands that secrete fluids, such as the salivary glands in the mouth and the tear glands in the eyes. The white blood cells injure the glands, resulting in a dry mouth and dry eyes — the hallmark symptoms of this syndrome." [3]

Irritable Bowel Syndrome

Irritable bowel syndrome is by definition a disease of unknown etiology and it is associated with abdominal pain, bloating, diarrhea, and constipation. It is also associated with inflammation of the mucosal lining of the intestines. One author suggests that 15% of IBS may be related to a prior infection. "Recent studies indicate that inflammatory processes involving the gastrointestinal tract are strongly correlated with IBS. Acute bacterial gastroenteritis has been linked with the onset of symptoms in approximately 15% of patients diagnosed with IBS; these cases have been called postinfectious IBS. Organisms commonly associated with postinfectious IBS include the foodborne pathogens Campylobacter, Escherichia coli, Salmonella, and Shigella. The pathologic changes associated with postinfectious IBS are likely due to inflammatory reactions induced by the infecting organisms. Postinfectious IBS should be recognized as a potential long-term consequence of foodborne gastroenteritis."^[16] IBS is largely considered an inflammatory disease of unknown etiology, although may theories exist as to what causes it. One subcategory of irritable bowel disease is Small Intestinal Bacterial Overgrowth (SIBO) syndrome.^[17][18] SIBO is present when gastrointestinal symptoms such as bloating correlate with breath tests positive for hydrogen or methane gas production, or with cultures from the small intesine which indicate overgrowth of bowel flora.^[19] Another category of irritable bowel disease, and a chronic inflammatory disease is Crohn's Disease. Some research suggests that Crohn's Disease is an infectious disease caused by Mycobacterium avium paratuberculosis, while the standard theory is that Crohn's is an autoimmune disease or a genetic dysfunction. As one review says, "The etiology of IBD is poorly understood, but autoimmune-disturbance has been suggested to play an important role in this incurable disease."^[20]

Gastroenteritis

Gastroenteritis is frequently an inflammatory disease of unknown etiology. Often no diagnosis can be made between a pathogen caused gastroenteritis or symptoms caused by a food allergy. Often the cause simply remains unknown even when extensive testing is done. Gastroenteritis of unknown etiology is often deadly, suggesting the need for better and more rapid diagnostic techniques. One articles says, "Gastroenteritis of unknown etiology (GUE) is a significant cause of mortality in the United States."^[21]

Graves' disease

Graves' disease is an inflammatory disease of unknown etiology that causes hyperthyroidism. The body incorrectly produces antibodies to the receptor for thyroid-stimulating hormone. These antibodies then stimulate thyroid hormone production. The trigger, if there is one, that starts the inflammatory process is unknown. A genetic predisposition may be present.^[22][23] It is speculated that some infectious agents, such as Yersina enterocolitica and retroviruses are triggers for Graves' disease (PMID 8491150). Enteroviruses are not linked to the etiology of Graves' disease.^[24]

Multiple Sclerosis

Multiple sclerosis is an inflammatory disease of unknown etiology in which white blood cells, called T cells, attack parts of the central nervous system.^[25]

See also

• List of syndromes and diseases with unknown etiologies