Complement-fixing platelet autoantibodies in autoimmune thrombocytopenia

A 16-year-old male patient is described with chronic autoimmune thrombo-cytopenic purpura and, after two years, “warm” autoimmune hemolytic anemia (Evans syndrome) who transiently developed complement-fixing platelet autoantibodies. The autoreactivity of these antibodies was established by quantitative complement fixation as well as by absorption and elution studies using autologous platelets. We believe this to be the first documented case with this very rare and peculiar type of platelet autoantibody.     

Acute autoimmune thrombocytopenia

Childhood acute autoimmune thrombocytopenia is defined as a bleeding disorder in otherwise healthy children caused by transient destruction of platelets. It is benign, presenting mostly with skin purpura and minor bleeds. The diagnosis requires information about previous infections or immunizations, a physical examination looking for signs or symptoms for other causes of thrombocytopenia and a complete blood count with examination of the peripheral blood smear focusing on the number and morphology of platelets. Bone marrow examination is indicated only when in doubt and should be considered if prednisone therapy is planned. A threshold platelet count dividing high- and low-risk groups in immune thrombocytopenia (ITP) is not known because of problems with platelet counting in thrombocytopenia and the lack of clinical data. Immunoglobulins or glucocorticoids increase the platelet count, probably by blockage of the phagocytic monocyte-macrophage system. However, it is unclear whether this increase influences bleeding or mortality or whether the disadvantages of these medications might outweigh their benefits.     

Platelet autoantibodies and lupus-associated thrombocytopenia

To characterize the antigenic targets of anti-platelet antibodies (APA) found in systemic lupus erythematosus (SLE)-associated thrombocytopenia, 48 patients with immune thrombocytopenia and SLE were compared with 20 patients with SLE who had never been thrombocytopenic. Both cases and controls were tested for circulating APA by an indirect platelet suspension immunofluorescence assay (PSIIFT) and by indirect monoclonal antibody specific immobilization of platelet antigens (MAIPA). A direct platelet suspension immunofluorescence assay (PSIFT) was also used for antibodies bound to platelets in vivo in thrombocytopenic patients; 13 of them with high titres of platelets-bound APA were investigated by direct and indirect MAIPA and platelet eluate analysis. Circulating APA were detected by PSIIFT in 88% of cases and 55% of controls (P = 0.0066) and platelet-bound antibodies were detected by PSIFT in 90% of cases. Indirect MAIPA detected specific APA (mainly directed against GpIIbIIIa) in 36% of cases and only 5% of the controls (P = 0.0076). Nine out of the 13 fully investigated thrombocytopenic patients (69%) had a positive direct MAIPA and/or APA detected in platelet eluates. In conclusion, the production of specific anti-platelet autoantibodies, mainly directed against GpIIb/IIIa, and their binding to platelet membrane plays an important role in the pathogenesis of SLE-associated thrombocytopenia.     

Platelet-bound IgM in autoimmune thrombocytopenia

Elevated levels of platelet-bound IgG (PA-IgG) are a feature of autoimmune thrombocytopenia (ATP), but it is well documented that this does not occur in all cases. This has led us to investigate the role of platelet-bound IgM (PA-IgM) in these patients using a quantitative enzyme-linked immunosorbent assay (ELISA). Forty-five determinations of PA-IgM and PA-IgG were done on 24 patients with ATP. Elevated levels of PA-IgM were found in 93.3% of the determinations, while PA-IgG was elevated in only 71.7%. In 64.4% of determinations, both were elevated. Elevated PA-IgM or PA-IgG alone occurred in 28.9% and 6.7% of determinations, respectively. These results show the hitherto unrecognized frequent involvement of PA-IgM in ATP and suggests that a complex interrelationship exists between the two immunoglobulin classes in ATP. Some of the possibilities that might explain this interrelationship are discussed.     

Non-thyroid autoantibodies in autoimmune thyroid disease

Autoimmune thyroid disease is frequently accompanied by other organ-specific and non-organ-specific diseases, most likely because there is sharing of genetic and possibly environmental susceptibility factors. These associations are well recognized in the autoimmune polyglandular syndromes; autoimmune thyroid disease is one of the three major endocrinopathies in the type 2 syndrome and occurs in around 4% of type 1 patients. This review considers the frequency of disease-specific autoantibodies in patients with thyroid autoimmunity and briefly examines the role of such antibodies in performing screening for the associated conditions. Recommendations are made for using such autoantibody tests in the setting of patients with autoimmune thyroid disorders, and also for the utility of screening for thyroid autoimmunity in patients with pernicious anaemia, Addison's disease, coeliac disease, primary biliary cirrhosis, myasthenia gravis, lymphocytic hypophysitis, systemic lupus erythematosus and rheumatoid arthritis. At present, however, there are no large-scale trials that have shown the cost-benefit ratio of autoantibody screening for autoimmunity screening, and clinicians must use individual judgement combined with heightened awareness to identify who to test.     

Pathophysiology and thrombokinetics in autoimmune thrombocytopenia

Studies that have measured platelet survival by autologous platelet labeling with (111)In and (51)Cr have differed in their results. Although all studies have revealed a significant decrease in platelet life span, the rates of platelets entering the circulation, a calculated and inferred determination, have been found to be moderately decreased to as much as five times normal. Several mechanisms have been proposed to explain an apparent decrease in platelet production, including a true decrease due to damage to the megakaryocytes by autoantibody, versus a decrease only in 'effective' production due to intramedullary destruction by the reticuloendothelial system. Recently, the identification of the cytokine, thrombopoietin, has allowed the evaluation of another aspect of the pathophysiology of thrombocytopenic states. Megakaryocyte growth factor levels are increased 10 to 20 times in patients who are thrombocytopenic due to chemotherapy or aplastic anemia, but may be decreased, normal, or only modestly raised in patients with immune platelet destruction. Autologous platelet survival measurements, prior to and while on therapy with a stable platelet count, reveal that removal of part of the reticuloendothelial system with splenectomy leads to increased platelet survival and platelet number. Similar studies reveal that corticosteroid treatment for immune thrombocytopenic purpura (ITP) effectively increases the rate of platelet production but does not change platelet survival. It may be that other therapies are effective by a combination of these mechanisms. Stimulation of thrombopoietin production or administering exogenous cytokine may have a role to play in future management of patients with ITP.     

Paraneoplastic autoimmune thrombocytopenia in solid tumors

Immune-mediated hematological diseases are rare, but typical paraneoplastic syndromes. We have critically analyzed 68 published cases of an association of autoimmune thrombocytopenia (ITP) and solid cancers. Such cases occurred in a variety of cancers. They were most common in patients with lung and breast cancer, very rare in prostate cancer, but relatively common in renal cell and ovarian cancers. ITP occurred in about half of the patients concurrently with cancer, in about 25% prior to cancer and in others some time after diagnosis and treatment of cancer. In the latter patients ITP was either a sign of recurrence of cancer or had other causes. In most patients ITP responded to steroid treatment. There were only few patients who had a complete response of ITP after surgical removal or chemotherapy of the cancer and there was only one patient (ITP prior to cancer) in whom a long lasting complete remission of ITP after cancer resection could be ascribed solely to cancer resection. We believe that in patients with ITP a cancer-associated ITP has always to be considered, but an extensive search for a present or future cancer is not indicated unless there is laboratory or clinical suspicion of a malignant disease. In patients with cancer associated ITP cancer resection should be done in non-metastatic cases (after appropriate pretreatment). In metastatic cases steroids are probably the treatment of choice.     

自身免疫性糖尿病相关抗体检测的研究进展

自身免疫性糖尿病以T细胞介导的胰岛β细胞特异性损伤及循环中出现胰岛自身抗体为特征,自身免疫是其发病的中心环节,自身抗体是目前最可靠的1型糖尿病（T1DM）生物标志物,临床应用广泛,其中最值得关注的则是其在T1DM的诊断及预测方面的价值。胰岛素自身抗体种类繁多,各有特点,目前临床应用的主要抗体包括谷氨酸脱羧酶抗体（GADA）、胰岛素自身抗体（IAA）、胰岛素瘤相关蛋白2抗体（IA-2A）和锌离子转运蛋白8抗体（ZnT8A）。联合检测对T1DM的诊断及预测有重要意义。     

Prevalence of non-thyroid autoantibodies in autoimmune dysthyroidies

Organ- and non organ-specific autoantibodies can be detected in patients with AITD but large comparative studies have seldom been performed. This study evaluated the prevalence of anti-thyroid, -smooth muscle, -mitochondria, -parietal gastric cells, -salivary duct, -nuclear and -ds DNA autoantibodies assayed by indirect immunofluorescence in 224 patients with Graves' disease or Hashimoto's thyroiditis. Results evidenced a high prevalence of antinuclear antibodies, mostly of non homogenous fluorescence in Graves' (63.1%) and Hashimoto's patients (65.5%), as well as for antisalivary duct antibodies (55.2 and 75%). No positive anti-ds DNA were noticed. No correlation was found between antithyroid antibodies and the others. Different hypothesis could explain this observation which favours a general dysregulation of the autoimmune system.     

Immunogenetics of autoantibodies and autoimmune diseases

The genetic contribution to the development of autoimmune disease is most likely complex. Along with loci controlling histocompatibility antigens and T-cell receptor proteins, genes that encode autoreactive immunoglobulins may have an important role in the pathogenesis of rheumatoid arthritis and related autoimmune diseases. Although much previous work in this area has concentrated on human monoclonal paraproteins and autoimmune mouse strains, the studies reviewed here examine immunoglobulin genes in the normal human population and normal mouse strains as well as in patients with autoimmune disease. Taken together, these studies suggest that genetic control of the expression of autoimmunity in rheumatoid arthritis and related autoimmune disorders is complex and most likely involves multiple gene loci.     

Cyclic thrombocytopenia of apparent autoimmune etiology

Serial studies were performed in two patients with cyclic thrombocytopenia to investigate the pathogenesis of this disorder. Mean life span of autologous platelets when platelet levels were declining was subnormal (2.4 and 0.8 days), and megakaryocytes were abundant in the bone marrow during thrombocytopenia. Megakaryocyte colony- stimulating activity could not be detected in the serum of either patient at any point of their cycles. In each patient, total platelet- associated IgG varied inversely with platelet levels. Surface platelet- associated IgG was measured only in patient 2 and was significantly elevated (greater than 1,280 IgG molecules per platelet) at all stages of the cycle, even during thrombocytosis. However, the highest values were observed during thrombocytopenia. Platelet-bindable IgG in plasma declined to normal immediately before platelet levels began to rise. IgG eluted from the platelets of this patient reacted strongly with autologous and homologous platelets in contrast to a "mock eluate" prepared from platelets of a normal subject. The eluate from the patient's platelets reacted strongly with immobilized autologous and homologous glycoprotein IIb/IIIa complex and weakly with GPIb but not with isolated GPIIIa alone. In each patient the decline in platelet levels was significantly delayed following administration of intravenous gamma globulin 0.4 g/kg body weight for five days. These findings suggest that platelet-reactive autoantibodies are of pathogenic significance in some patients with cyclic thrombocytopenia.     

Cyclic thrombocytopenia associated with IgM anti-GPIIb-IIIa autoantibodies

Summary. We studied a female patient with cyclic fluctuation in platelet count following splenectomy for autoimmune thrombocytopenia. The cyclical fluctuation appeared to be in phase with her menstrual cycle and her platelet count was low during menses. Bone marrow examinations performed at the peak as well as the bottom of the platelet count showed normal or increased numbers of megakaryocytes. The patient's platelet count increased rapidly after intravenous gamma-globulin (IVIgG) therapy, suggesting that a failure of platelet production is unlikely to account for the cycle. Platelet-associated IgM (PAIgM) was markedly elevated, whereas PAIgG was normal at any stage of the cycle. MACE assay demonstrated that PAIgM contained IgM anti-glycoprotein (GP) IIb-IIIa autoantibodies. Comparison between MACE assay using untreated and EDTA-treated platelets at 3 7°C demonstrated that the platelet-associated IgM autoantibodies mainly recognized divalent cation-dependent conformation(s) of GPUb-IIIa. No antibodies were, however, detected in her serum. The levels of IgM anti-GPIIb-IIIa showed an inverse relationship with the platelet count. In spite of the marked increase in platelet count after IVIgG, however, the levels of IgM anti-GPIIb-IIIa remained elevated. These findings suggest that plateletassociated IgM anti-GPIIb-IIIa autoantibodies are of pathogenic significance in this patient.     

New autoantibodies and autoantigens in autoimmune hepatitis

The molecular characterization of the autoreactivities associated with autoimmune liver disease will improve their diagnosis and enhance understanding of their pathogenic mechanisms. Surprisingly, little is known about the nature of the major autoreactivities associated with type 1 AIH, including homogeneous ANA and antibodies to microfilaments [3]. Type 1 AIH is, however, the prototype of autoimmune liver disease [103].     

Idiopathic autoimmune thrombocytopenia and neutropenia in siblings

Familial incidences of autoimmune disorders involving red cells, white cells and platelets are rare. Two cases of autoimmune neutropenia and thrombocytopenia occurring in two adult brothers are reported here. One patient showed prompt recovery of white cells with steroids but needed IV IgG+ splenectomy for durable platelet recovery. His brother required splenectomy for durable recovery of white cells and platelets as he showed transient recovery with steroids and IV IgG.     

自身抗体在自身免疫性肝病中的预测价值

自身抗体作为自身免疫性肝病的诊断标志物已经在临床上得到了广泛应用,但其在病情严重程度及预后判断方面的价值报道并不多,事实上某些自身抗体除本身的诊断价值外,还具有预测病情的作用：如抗可溶性肝抗原抗体、抗肌动蛋白抗体、抗肝细胞溶质抗原Ⅰ型抗体、抗去唾液酸糖蛋白受体抗体、抗染色体抗体、抗环瓜氨酸多肽抗体和抗肝肾微粒体Ⅲ型抗体与自身免疫性肝炎的发生、发展及恶化有一定的相关性,其中抗可溶性肝抗原抗体与某些自身免疫性肝炎患者严重肝组织学改变、长期维持治疗、停药后再度恶化以及肝衰竭的发生相关;抗gp210抗体、抗Sp100抗体和抗着丝点抗体在原发性胆汁性肝硬化中有一定的预测意义,其中抗gp210抗体可提示原发性胆汁性肝硬化患者有较严重的界面性肝炎、小叶炎症以及易进展为肝衰竭等。     

Malignant histiocytosis associated with autoimmune thrombocytopenia

We describe a patient with malignant histlocytosis whose serum contained an autoantlbody against platelet protein. The patient was admitted because of nasal bleeding and high-grade fever. The clinical course was fulminantly progressive and terminated with cerebral hemorrhage. Bone marrow aspirate showed the proliferation of large atypical cells, some of which exhibited phagocytic activity. At postmortem examination, there was diffuse infiltration of these atypical cells In the liver, spleen, kidney, and bone marrow. Morphological, cytochemlcal, immunohistochemlcal, and genotypic characteristics suggested that the proliferating cells were derived from the monocyte-rnacrophage system. Western blot analysis revealed the presence of autoantibody against an ～88 kd molecule of platelet proteins. Although the relationship of cause and effect remains to be clarified, this autoantibody appeared to have stimulated thrombophagocytosls of the neoplastic cells. © 1994 Wiley-Liss, Inc.