Shomi:
Any virus or bacteria can potentially cause ITP. Sometimes treating can ressolve it, but not often. I doubt the doctor would have tested your wife for this; it's not a common diagnostic test for ITP. You could ask for it, but I don't know what sort of response you will get. Sometimes, there isn't an identifiable underlying cause.
See the following theories regarding the mechanisms for ITP.
ITP Mechanism of Action
ITP is an autoimmune disease. The term “autoimmune disease” covers a range of different diseases and different mechanisms, each of which share the feature that the immune system incorrectly recognizes self as an antigen. Some autoimmune diseases are organ-specific, such as type I insulin-dependent diabetes mellitus, which affects the pancreatic islets. Other autoimmune diseases are systemic, such as systemic lupus erythematosus. In some autoimmune diseases, the autoantibody binds to a receptor, turning the receptor on. For example, in Graves’ disease, the autoantibody binds to a thyroid-stimulating hormone receptor on thyroid cells, stimulating excessive production of the thyroid hormone. In other autoimmune diseases, the autoantibody blocks a receptor. For example, in myasthenia gravis, autoantibodies block neuromuscular transmission. Some autoimmune diseases are driven by autoreactive T cells, and can lead to extensive tissue damage (for example, Multiple Sclerosis). Some autoimmune diseases have multiple immunopathogenic mechanisms (for example, Rheumatoid arthritis).
The disease ITP describes a specific physiological state: the patient has a low platelet count, and other conditions or diseases that would lead to a low platelet count have been eliminated. As described in the “Diagnosis” section above, ITP is primarily diagnosed by the exclusion of other disease types.
As such, there may be multiple possible mechanisms underlying ITP. There are broadly two types of mechanisms found in the literature: autoantibodies targeted against platelets, and autoantibodies targeted against megakaryocytes (the cells that produce platelets). It may be that one mechanism will ultimately be proven to be more correct than the other. More likely, some ITP conditions are due to one mechanism of action, and other ITP conditions are due to the other. Indeed, based on the false negatives of the laboratory tests described in the “Diagnosis” section, one can infer that multiple mechanisms of action could account for the collection of maladies that are grouped under the common disease name ITP.
Autoantibodies Against Platelets
By this classic autoimmune mechanism, the autoantibodies trigger the destruction of their target, the platelets. This mechanism is the most commonly cited in literature, and likely represents the majority of ITP cases.
Studies as early as the 1950's showed that thrombocytopenia could be induced by transfusing blood from a patient with chronic ITP into a normal volunteer. Further research isolated the substance in ITP patients that caused the destruction of platelets, and led to its identification as an autoantibody.
When autoantibodies bind to platelets, the platelets are marked for destruction in two ways: via phagocytosis and via complement activation. In phagocytosis, the platelets are marked for destruction by the Fc region of the bound immunoglobulins. For example, the platelets bound by IgM autoantibodies fix C3, and are cleared by CR1- and CR3-bearing macrophages, often in the fixed mononuclear phagocytic system. The macrophages phagocytose and destroy the platelets. This clearance often occurs in the spleen, but can also occur in the bone marrow or liver. The bound immunoglobulins can also fix complement, leading to the formation of a membrane-attack complex on the platelet. This process also leads to platelet destruction.
Technically, the immunopathogenic mechanism of ITP is a Type II antibody to cell-surface antigen. The cell surface antigen is most likely a glycoprotein complex on the surface of the platelet. As indicated from the “Diagnosis” section, the most common two complexes that serve as antigens are glycoprotein IIb/IIIa (a combination of platelet glycoprotein IIb and platelet glycoprotein IIIa) and glycoprotein Ib/IX (a combination of platelet glycoprotein Ib and platelet glycoprotein IX). Some forms of ITP may target other glycoprotein complexes that are not yet identified.
According to this model, the platelets – tagged with autoantibodies – are primarily removed from circulation via phagocytosis in the spleen. The spleen is the primary location of removal for several reasons. At any given time, approximately one third of the body’s circulating platelets are in the spleen. Moreover, much of the autoantibody production occurs in the spleen; thus, platelets in the spleen are exposed to high concentrations of autoantibody. In addition, the spleen is rich in macrophages that phagocytose cells that are marked for destruction by antibodies. Based on the role of the spleen in ITP, it should not be surprising that removal of the spleen often results in the cure of many ITP patients (treatments are discussed in more detail in the “Treatments” section of this paper).
There is some evidence that in some forms of ITP, the platelets are not only targeted in the blood. As noted by Robert McMillan MD of The Scripps Research Institute, the bone marrow can increase the production of platelets up to 6 to 8 times normal, if necessary. Yet in many ITP patients, platelet production is less than would be expected given the ongoing platelet destruction. Based on this observation, Dr. McMillan suggests that “the autoantibody, in some patients, may inhibit platelet production or destroy platelets in the bone marrow before they can be released into the blood.” For such patients, spleen removal would not help fight the disease at all. Dr. McMillan’s suggestion is also consistent with the second model of ITP mechanism, where the autoantibodies are directed against the megakaryocytes.
Autoantibodies Against Megakaryocytes
A recent article in journal Blood (February, 2004) suggests that the root cause of ITP could be the inhibition or confounding of platelet production at the megakaryocyte level. The investigators compared the blood from healthy donors and ITP patients. They found that blood from 12 of the 18 ITP patients showed a significant decrease in megakaryocyte production. Moreover, blood from ITP patients showed a decrease in the total numbers of megakaryocytes produced during the incubation period. Megakaryocytes in ITP patients produced fewer platelets per megakaryocyte than those in healthy donors. The authors suggest that these results are most likely due to ITP antibodies.
This study is supported by other pieces of evidence. For example, according to the Platelet Disorder Support Organization (PDSO), studies have shown that 30% to 50% of patients with ITP have a reduced rate of platelet production. Researchers in the Netherlands have found evidence that the reduced platelet production may be associated with injured or abnormal megakaryocytes. According to the researchers, the megakaryocytes in ITP patients were surrounded by neutrophils and macrophages, indicating an inflammatory response against the megakaryocytes. In addition, the megakaryocytes appeared to be displaying characteristic signals similar to the signals of dying cells. Based on these findings, the researchers concluded that the lowered platelet count in ITP could possibly be due to the action of autoantibodies against the megakaryocytes.
Overall, the mechanism of action of ITP is still being studied and understood. It could be that ITP represents a collection of specific diseases, each with a slightly different mechanism. It could also be that the autoantibodies act in multiple ways. For example, platelets and megakaryocytes share some surface glycoproteins. If an autoantibody recognizes one of these “shared” glycoproteins as its antigen, then the autoantibody would bind to both platelets circulating in the blood as well as megakaryocytes in the bone marrow.
It is the opinion of this author that ITP does indeed represent a collection of mechanisms of action. Based on the lack of a diagnostic test, as well as the wide range of severities of the cases, it appears as if not all cases of ITP are created equal. For some of the mild cases, just the platelets may be targeted. In those cases, the megakaryocytes are able to partially compensate with increased platelet production. Such patients can have chronic but stable ITP, with low platelet counts at a safe level (upwards of 100,000 platelets per milliliter of blood). In severe cases, the autoantibody may be directed against an antigen that is both on platelets as well as megakaryocytes. In those cases, platelet production is greatly diminished, and the patient must undergo treatment to avoid the dangers of internal bleeding.
Causes of Autoimmunity in ITP
Modern science does not know what causes autoimmunity in ITP.
There are, broadly, three theories on the possible causes of autoimmune diseases: the “Microbial Trigger Theory,” the “DNA Damage Theory,” and the “Molecular Mimicry Theory.” They are each outlined below. It is likely that an autoimmune disease develops due to a combination of events.
Microbial Trigger Theory
This theory was explored in Science News in the article "Microbial Trigger for Autoimmunity?" Lymphocytes exist in the body that are autoreactive, yet remain inactive. Researchers found that in mice, these dormant cells can become activated if the cells are near a bacterial infection. When the body fights the bacterial infection and interleukin-12 is created, the interleukin-12 creates an array of additional compounds specific to the pathogen. These anti-microbial compounds released near the infection site could accidentally activate a dormant, self-reactive lymphocyte. If the dormant lymphocyte targets platelets, then the microbial invasion may have triggered autoimmunity against platelets.
DNA Damage Theory
According to this theory, autoimmune diseases are developed due to a genetic defect that arises in a key part of the immune system.
There are many complex processes involved with avoiding autoimmunity. According to clonal deletion, T cells that react to self-molecules in the thymus are eliminated. If the presentation of self-antigen and subsequent elimination of autoreactive T cells does not proceed perfectly, a self-reactive T cell could mature, and an autoimmune disease could develop. Autoreactive T cells that are not eliminated in the thymus can be suppressed through other mechanisms. However, when those suppression mechanisms break down, an autoimmune disease can develop.
If a process becomes altered because of a genetic defect, then there is increased risk of the development of an autoimmune disease. The genetic defect could be due to free radical damage or through other causes of somatic genetic mutation. 27 The defect could also be genetic, as a small nucleotide polymorphism in one or both alleles could make an individual more susceptible to acquiring an autoimmune disease.
Indeed, there is evidence that some individuals are genetically more prone to autoimmune diseases than others. A twins study was conducted for several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and IDDM. Monozygotic twins were compared with dizygotic twins. For each disease, the monozygotic twins showed disease concordance 20% of the time, compared with only 5% for dizygotic twins. In particular, it is thought that the MHC genotype is particularly important.
Molecular Mimicry Theory
According to this theory, autoimmune diseases are caused when pathogens are detected in the body that are similar to self-molecules. Lymphocytes are activated to target the intended antigen, but as they attack the pathogen, they also attack the similar self-molecules. 30 By itself, it is unlikely that this theory explains the onset of an autoimmune disease. However, molecular mimicry may be an important factor when combined with either the Microbial Trigger Theory or DNA Damage Theory.
Autoimmunity often occurs spontaneously in patients, and science does not know what events trigger the onset of the disease. It is likely that autoimmune diseases arise from a confluence of factors. For example, in one experiment, it was shown that it is possible to induce an autoimmune disease through a combination of the three theories above. Genetically susceptible strains of animals (DNA damage) were injected with “self” tissues (Molecular Mimicry) mixed with strong adjuvants containing bacteria (Microbial Trigger). The combination of those events provoked autoimmunity.
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