Autoimmune Manifestations Following alloBMT

The pathogenesis of autoimmune manifestations post-alloBMT may be related to transfer of abnormal Band T-cell clones from the donor or to dysregulation of the newly developing immune system of donor origin in the host across minor or major histoin-compatibility barriers, frequently further perturbed by immunosuppressive agents administered to prevent or treat GVHD. The general immune imbalance seen during the first period following alloBMT, which may last several years, may contribute to an acceleration of autoimmune manifestation including organ specific autoimmune dysfunction. In addition cytomegalovirus (CMV) or possible other viral infections have been suggested to be possible important etiologies that may be associated with certain autoimmune phenomena post-alloBMT [45]. CMV disease is associated with various autoimmune manifestations including autoimmune hemolytic anemia, autoimmune granulocytopenia and the formation of autoantibodies [46]. It was found that CMV induces a CD13-specific autoimmunity. CMV-associated host protein CD 13 is immuno-

genie during CMV infection in alloBMT [45], Moreover, CMV-induced CD13-specific autoimmunity contributes to tissue damage in chronic graft vs host disease (cGVHD) [46], A specific response against autoantigens associated with infectious virus particles was recently also suggested as a possible mechanism to explain virus-induced autoimmune manifestations.

Several autoimmune manifestations have been described following alloBMT. To start with, cGVHD may be considered as an autoimmune disease or rather iatrogenic autoimmune-like disease [47]. Patients with cGVHD suffer from symptoms of xerostomia and xerophtalmia, which are indistinguishable from Sjogren's syndrome, a known autoimmune disorder [48— 50]. In this syndrome, autoreactive T cells (with slight predominance of CD8+ over CD4+ cells are infiltrating the major salivary glands and autoreacting against ductal epithelial cells expressing HLA-DR antigens [48]. In addition, cGVHD bears clinical similarities to connective tissue diseases, which are characterized by a spectrum of autoantibody formation [49]. The most common autoantibody detected in cGVHD patients is IgM anticytoplasmic factor occurring in 37% of the patients with cGVHD following alloBMT [49]. Thrombocytopenia and lymphopenia are known manifestations of cGVHD, even when all hematopoietic cells are of donor origin. In addition to immune thrombocytopenia, autoimmune hemolytic anemia and autoimmune neutropenia have been reported following alloBMT independently of cGVHD [51-56], Lee et al. [51] reported a 38-year-old man who developed idiopathic thrombocytopenic purpura (ITP) 8 months following alloBMT, responding to intravenous anti-D immunoglobulin. Autoimmune destruction of platelets has been suggested as a possible mechanism and positive antiplatelet autoantibodies have been reported [52]. In some of the cases, the antiplatelet autoantibodies have been attributed to clonal B-cell expansion, demonstrated by using the immunoglobulin heavy chain rearrangement PCR technique [52], Increased susceptibility to infections post-alloBMT may result in polyclonal antibody responses, like chronic inflammation, which may be associated with autoimmune syndromes that may be caused by cross-reacting pathogenic antigens.

Antibody mediated neutropenia has been also reported post-alloBMT [53], This syndrome which is distinct from conventional graft rejection, should be included in the differential diagnosis of neutrope nia following alloBMT. In contrast to post-alloBMT neutropenia due to graft rejection, intrinsic stem-cell failure, infections, GVHD, relapse or drug-induced myelosuppression antibody-mediated neutropenia usually responds well to treatment with corticosteroids, plasma exchange, and intravenous immunoglobulin or splenectomy [53]. Autoimmune hemolytic anemia has also been reported following alloBMT. In some cases, autoimmune pancytopenia including autoimmune thrombocytopenia, neutropenia and anemia have been reported [54]. The autoimmune pancytopenia may be due to transfer of antibodies of donor origin and may thus respond to immunosuppressive therapy [55].

Autoimmune hemolytic anemia due to warm antibodies lasting 15 months following alloBMT was reported in a 10-year-old boy with familial Wiskott-Aldrich syndrome [56]. Interestingly, this patient developed a second possible autoimmune manifestation, autoimmune adrenal insufficiency, characterized with diarrhea, fatigue, polyuria and hyperpigmenta-tion of the skin and mucosa as well as electrolyte imbalance and absent Cortisol response to adrenocorticotropic hormone (Addison disease) with positive adrenal antibodies 10 years later [56], Addison disease is only one example of autoimmune endocrinopa-thy that have been reported following alloBMT. The most prevalent autoimmune endocrinopathy following alloBMT is autoimmune thyroid abnormalities [57-60]. The most common finding is compensated hypothyroidism with elevated TSH and normal T3 and T4 levels [57, 58]. Clinical hypothyroidism occurs in 1.1% of the patients post-alloBMT usually in the first 2 years post-transplant and in some cases it is associated with cGVHD [57]. In other cases, autoimmune thyroiditis is associated with other autoimmune diseases [59]. Kishimoto et al. [60] reported a case of autoimmune hyperthyroidism post-alloBMT in a patient who previously developed another autoimmune disease, palmoplantar pustular psoriasis. In some of the cases, the autoimmune hypothyroidism was due to anti-thyroglobulin antibodies that did not exist pre-BMT and was transferred from the donor to the recipient by the alloBMT. The donor may have no history of thyroid diseases and shown normal thyroid function while being positive for anti-thyroglobulin antibodies indicating a subclinical state [59], Autoimmune thyrotoxicosis has also been reported post-alloBMT [60]. In some of these cases, no autoimmune thyroid disease could be suspected prior to alloBMT and it is therefore conceivable that thyrotoxicosis resulted from transplantation of an abnormal clone of lymphocytes predisposed to the production of thyroid-stimulating autoantibodies, or alternatively, that genetically susceptible donor lymphocytes may have been stimulated by host antigens that may be released due to transplantation-induced tissue damage [58, 60]. Another example of organ specific autoimmune dysfunction post-alloBMT is type-I diabetes, which has been reported to be transferred by donor stem cells to the recipient in the course of alloBMT [61-63]. In one of the reported cases, both the male donor and HLA identical female recipient had insulin-dependent diabetes. The recipient was positive for islet cell antibodies post-alloBMT while negative results were obtained pre-alloBMT. Chimerism studies demonstrated 100% donor male cells, indicating transfer of insulin-dependent diabetes by the donor bone marrow cells as was also shown in experimental animals, indicating that spontaneous autoimmunity may be entirely a stem-cell disease [13].

Additional rare autoimmune manifestations that have been reported following alloBMT are: immunodeficiency that was associated with autoreactive T-cell receptor gamma delta-bearing lymphocytes [64], an-tiphospholipid syndrome [65] and cold agglutinin disease in which the pathogenic protein was monoclonal IgM-kappa with anti-Pr antigen specificity, probably derived from the engrafted donor lymphocytes [66]. Myasthenia gravis or related acute inflammatory demyelinating polyneuropathy is a devastating autoimmune disease also described following alloBMT [67-70]. In most but not all the reported cases, the underlying disease is severe aplastic anemia and most of the cases also suffered from cGVHD [67-69]. Other underlying diseases were CML and ALL [67]. In most of the cases, the diagnosis of myasthenia gravis was made based on clinical symptoms (proximal muscle weakness and ptosis) and the presence of antiacetyl-choline receptor antibodies [67], The haplotypes HLA B7, B35 and DR2 were commonly associated with such disease manifestations [67-69], The stem-cell donor may have no history of myasthenia gravis, while being positive for antiacetylcholine receptor antibody, indicating a subclinical or rather genetic susceptibility that may be expressed under favorable conditioning of immune instability in the recipient. In most of the cases, the recipient was negative for the antiacetylcholine receptor antibody prior to alloBMT, indicating adoptive transfer to the recipient by the alloBMT procedure. Another autoimmune neurological disease that was described following alloBMT is acute inflammatory demyelinating polyneuropathy resulting from autoreacting T cells that were probably sensitized in the host against peripheral nervous system myelin [70],

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