Presence Of Autoreactive Antibodies Research Articles

Autoimmune processes in neurological patients are much more common than presently suspected

Autoimmune encephalitides are seldom diseases. How rare they actually are, however, is not known. The low incidence combined with the problematic identification may dampen efforts of neurologists, to identify patients with unclear symptoms as suffering from autoimmune encephalitis. Here, we aim to obtain a better estimate, how many patients with autoimmune disorders should be expected among 100 inpatients in a conventional neurological department. From a total number of 2603 non-stroke patients attended in a 2-year period (2018–2019) 460 CSFs were obtained. From this collection 187 samples (40.7%, > 500 sections) could be analyzed with our immunocytochemical technique. Autoreactive antibodies were detected in 102 (55%) of these 187 CSF samples. Certainly, the presence of autoreactive antibodies does not necessarily indicate that the patient suffers from an autoimmune disease. Our data indicate that from roughly 2000 patients during 1 year about 125 patients with autoreactive CSF antibodies should be expected in a conventional neurological department. This represents the about 35-fold value of what is generally expected at present. Being aware of this high incidence may intensify the efforts of neurologist to identify patients with any type of autoimmune encephalitis. This will be beneficial for patients, because they often profit from immunomodulatory therapy. Interestingly, some CFSs from our patients react with the CA2 subdivision of the hippocampus. While long neglected, recent research places this area into an important position to influence hippocampal network physiology. Autoreactive antibodies in the CSF may disturb the function of CA2 neurons, thereby explaining some neuropsychiatric symptoms in patients with autoimmune encephalitides.

The immunodominant antibody response to Zika virus NS1 protein is characterized by cross-reactivity to self.

Besides antigen-specific responses to viral antigens, humoral immune response in virus infection can generate polyreactive and autoreactive antibodies. Dengue and Zika virus infections have been linked to antibody-mediated autoimmune disorders, including Guillain-Barré syndrome. A unique feature of flaviviruses is the secretion of nonstructural protein 1 (NS1) by infected cells. NS1 is highly immunogenic, and antibodies targeting NS1 can have both protective and pathogenic roles. In the present study, we investigated the humoral immune response to Zika virus NS1 and found NS1 to be an immunodominant viral antigen associated with the presence of autoreactive antibodies. Through single B cell cultures, we coupled binding assays and BCR sequencing, confirming the immunodominance of NS1. We demonstrate the presence of self-reactive clones in germinal centers after both infection and immunization, some of which present cross-reactivity with NS1. Sequence analysis of anti-NS1 B cell clones showed sequence features associated with pathogenic autoreactive antibodies. Our findings demonstrate NS1 immunodominance at the cellular level as well as a potential role for NS1 in ZIKV-associated autoimmune manifestations.

MTOR signaling is essential for the development of thymic epithelial cells and the induction of central immune tolerance

ABSTRACTThymic epithelial cells (TECs) are critical for the establishment and maintenance of appropriate microenvironment for the positive and negative selection of thymocytes and the induction of central immune tolerance. Yet, little about the molecular regulatory network on TEC development and function is understood. Here, we demonstrate that MTOR (mechanistic target of rapamycin [serine/threonine kinase]) is essential for proper development and functional maturation of TECs. Pharmacological inhibition of MTOR activity by rapamycin (RPM) causes severe thymic atrophy and reduction of TECs. TEC-specific deletion of Mtor causes the severe reduction of mTECs, the blockage of thymocyte differentiation and output, the reduced generation of thymic regulatory T (Treg) cells and the impaired expression of tissue-restricted antigens (TRAs) including Fabp2, Ins1, Tff3 and Chrna1 molecules. Importantly, specific deletion of Mtor in TECs causes autoimmune diseases characterized by enhanced tissue immune cell infiltration and the presence of autoreactive antibodies. Mechanistically, Mtor deletion causes overdegradation of CTNNB1/Beta-Catenin due to excessive autophagy and the attenuation of WNT (wingless-type MMTV integration site family) signaling in TECs. Selective inhibition of autophagy significantly rescued the poor mTEC development caused by Mtor deficiency. Altogether, MTOR is essential for TEC development and maturation by regulating proliferation and WNT signaling activity through autophagy. The present study also implies that long-term usage of RPM might increase the risk of autoimmunity by impairing TEC maturation and function.

Interferon beta 1a treatment induces the presence of autoreactive antibodies (ARAB) in patients with relapsing–remitting multiple sclerosis (RRMS)

Interferon beta 1a treatment induces the presence of autoreactive antibodies (ARAB) in patients with relapsing–remitting multiple sclerosis (RRMS)

CD34+ gene expression profiling of individual children with very severe aplastic anemia indicates a pathogenic role of integrin receptors and the proapoptotic death ligand TRAIL

BACKGROUND Very severe aplastic anemia is characterized by a hypoplastic bone marrow due to destruction of CD34(+) stem cells by autoreactive T cells. Investigation of the pathomechanism by patient-specific gene expression analysis of the attacked stem cells has previously been impractical because of the scarcity of these cells at diagnosis. Employing unbiased RNA amplification, patient-specific gene expression profiling was carried out for CD34(+) cells from patients newly diagnosed with very severe aplastic anemia (n=13), refractory anemia (n=8) and healthy controls (n=10). These data were compared to profiles of myelodysplastic disease (n=55), including refractory anemia (n=18). To identify possible targets of autoimmune attack, presence of autoreactive antibodies was tested in pre-therapeutic sera of patients with very severe aplastic anemia (n=19). CD34(+) gene expression profiling distinguished between healthy controls, children with aplastic or refractory anemia and clonal disease. Interferon stimulated genes such as the apoptosis inducing death ligand TRAIL were strongly up-regulated in CD34(+) cells of patients with aplastic anemia, in particular in patients responding to immunosuppressive treatment. In contrast, mRNA expression of integrin GPVI and the integrin complexes GPIa/IIa, GPIIb/IIIa, GPIB/GPIX/GPV was significantly down-regulated and corresponding antibodies were detected in 7 of 11 profiled patients and in 11 of 19 aplastic anemia patients. CONCLUSIONS As a potential diagnostic tool, patient-specific gene expression profiling of CD34(+) stem cells made it possible to make the difficult differential diagnosis of most patients with aplastic and refractory anemia. Profiling indicated a prognostic correlation of TRAIL expression and patient benefit from immunosuppressive therapy. Downregulation of integrin expression and concurrent presence of autoreactive anti-integrin-antibodies suggested a previously unrecognized pathological role of integrins in aplastic anemia.

Immunology of Endometriosis

Endometriosis is a common condition with a varied phenotype. Symptomatic cases have been associated with progesterone resistance and dysregulated cytokine production in both ectopic and eutopic endometrium. In at least some cases, this seems to be associated with chronic local inflammation and antibody self-reactivity. Coexistence of endometriosis with autoimmune disease has been documented in a small number of cases, and the presence of autoreactive antibodies in the serum of some patients with endometriosis is commonly reported. This paper briefly reviews the association between endometriosis and autoimmune disease and describes the potential role of inflammation in the development of immunologic self-reactivity in these patients.

Presence of autoantibodies in sera of patients with sporadic idiopathic hypoparathyroidism

目的 探讨散发性特发甲状旁腺机能减退症患者体内是否存在自身免疫性抗体.方法 对散发性特发甲状旁腺机能减退症患者26例、其直系亲属112例以及健康对照者60例,采用间接免疫荧光技术检测抗甲状旁腺自身免疫性抗体,同时检测血清钙、磷、镁、甲状旁腺激素含量.结果 散发性特发甲状旁腺机能减退症患者血清中抗甲状旁腺自身抗体阳性10例,阳性率为38%,明显高于直系亲属的10%(χ2=13.42,P＜0.01)和健康对照者的7%(χ2=13.46,P＜0.01).患者以女性为主(19/26),抗体阴性患者平均病程0.5～7年(中位数为2.2年),较抗体阳性患者平均病程0.5～4.5年(中位数为1.75)有延长的趋势;血清甲状旁腺激素水平在抗体阴性患者中为(7.06±2.06)ng/L,较抗体阳性患者的(8.86±2.86)ng/L有降低的趋势,差异无统计学意义(P=0.74).结论 散发性特发甲状旁腺机能减退症患者体内有抗甲状旁腺的自身免疫性血清学证据,抗甲状旁腺抗体的出现提示该病与自身免疫有关。

Immune recognition of human Hsp60 by Lyme disease patient sera

Members of the Hsp60 family of microbial heat shock proteins frequently serve as immunodominant antigens and immunological responses to these highly conserved proteins have been implicated in the pathology of a number of autoimmune diseases and inflammatory processes associated with microbial infection. In the present study, sera from patients with Lyme disease were examined by Western blot analysis for the presence of IgG against Borrelia burgdorferi antigens and for autoreactive IgG against recombinant human Hsp60 (huHsp60). These results were then compared to those obtained using sera from normal healthy controls, patients with a variety of acute non-spirochete infections, and patients with rheumatoid arthritis (RA). The results indicate a high incidence of autoreactive antibodies against huHsp60 in the sera of Lyme disease patients (67.9%) and patients with RA (75%). Positive reactivity was observed at lower rates in sera from healthy controls (25%) and sera from patients with acute non-spirochete infections (38%). Together the data suggest an association between the presence of autoreactive antibodies against huHsp60 and infection with B. burgdorferi. A similar association may exist between the presence of autoreactive antibodies against huHsp60 and RA.

Identification of Autoreactive Lymphocytotoxic Antibodies in Sensitised Dialysis and Kidney Transplant Patients

Autoreactive lymphocytotoxic antibodies, which have been found in sensitised dialysis patients, are generally not considered to be harmful to a renal allograft. In this work the presence of such autoreactive antibodies was investigated in the following groups of sensitised endstage renal disease patients: (a) dialysis patients waiting for a first kidney transplant, (b) kidney transplanted patients, and (c) dialysis patients with a previous failed graft. Only sera from the above patients which showed high reactivity (greater than 30%) against peripheral blood lymphocytes of a random cell panel (R-PBL), were screened for the presence of autoreactive lymphocytotoxic antibodies, by testing at different temperatures against autologous T lymphoblasts (PHA-ATL) and EBV-induced autologous B lymphoblasts (EBV-ABL). The results showed that both blood transfusions, and viral infections such as cytomegalovirus (CMV), correlated with the presence of autoreactive antibodies, and that in addition, by using PHA-ATL and/or EBV-ABL as absorbing reagents, it was possible to remove the antibodies. These absorption procedures allowed the identification of the presence of autoreactive antibodies alone or in combination with other alloantibodies.