Serologic Evidence Of Autoimmunity Research Articles

#6395 TUBULORETICULAR INCLUSIONS: A NEW PROGNOSTIC BIOMARKER IN KIDNEY TRANSPLANTATION

Abstract Background and Aims Tubuloreticular inclusions (TRIs) seen on electron microscopy (EM) are classically associated with lupus nephritis (LN) and systemic viral infections in native biopsies. Traditionally a marker for enhanced type I interferon expression, little is known about their significance post-transplant. We aimed to look at a large cohort of transplant biopsies showing TRIs to investigate associations and outcomes. Method A retrospective analysis was performed on two prospective databases; an in-centre transplant registry and a histopathology database holding data on all kidney biopsies performed at our centre. All patients biopsied since 2015, who had EM examination were included. Where patients had more than one biopsy showing a TRI the earliest one was included. Demographic, clinical and transplant data was collected from the laboratory records. Results 2283 kidney transplant biopsies were performed between January 2015 and November 2022; 1898 (83.1%) had EM performed. Of 1898 with EM, 176 (10.8%) had evidence of TRIs. Of 176 patients, 34% were female, the median age was 52.2 (38.9-59.4) years, 32% had underlying glomerulonephritis as their cause of ESKD, 65% were deceased donors and 75% were of non-white ethnicity. TRIs were associated with serological evidence of autoimmunity (16%), viral infections (26%) and donor specific antibodies (28%), with no association found in 41%. Rejection occurred in 49%, including 31% of patients with no recognised association with TRIs. Allograft outcomes were poor, with all-cause allograft survival and death-censored allograft survival of 66% and 60%, after a follow up of 1.9 +/− 1.8 years post index biopsy. A comparison with a matched control group is planned Conclusion In extension to previous work, we show that TRIs appear to be associated with alloimmunity. In this regard they may be a useful biomarker especially in cases where the diagnosis is unclear or biopsy findings are ‘subthreshold’. Irrespective of aetiology, TRIs are associated with poor outcomes and warrant further consideration.

Therapeutic Plasma Exchange in Treatment of Autoimmune Encephalitis: A Case Report

The present study highlights the Therapeutic Plasma Exchange in treatment of Autoimmune Encephalitis. Due to the similarities in the clinical, imaging, and laboratory findings of many forms of autoimmune and infectious encephalitis, autoimmune encephalitis is frequently a difficult clinical diagnosis. Diagnosis of autoimmune encephalitis is based on the clinical course, serological evidence of autoimmunity, EEG changes, evidence of intrathecal inflammation in the cerebrospinal fluid and neuroimaging by MRI. In view of the suspected diagnosis of Autoimmune Encephalopathy with super refractory Status Epilepticus, Methylprednisolone was later added to the treatment. This case represents an interesting scenario of sero-negative encephalitis in which an early diagnosis could be made and treatment initiated in time.

Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans.

Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients. SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls. Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10-4 ). In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.

Chapter 14 - Autoimmune dementia and encephalopathy

Autoimmune dementia and encephalopathies (ADE) are complex disorders that can cause immune-mediated cognitive deficits and have confusing nomenclature. Presentation varies from acute limbic encephalitis to subacute or chronic disorders of cognition mimicking neurodegenerative dementia. It may occur as a paraneoplastic phenomenon or an idiopathic autoimmune phenomenon. The presence of a personal/family history of autoimmunity, inflammatory spinal fluid, serologic evidence of autoimmunity (neural or nonorgan-specific), or mesial temporal magnetic resonance imaging abnormalities are clues to diagnosis. Bedside cognitive assessment and/or detailed neuropsychologic testing are useful. Neural-specific autoantibodies, mostly discovered in the past two decades, may bind antigens on the cell surface (e.g., N-methyl-d-aspartate receptor autoantibodies) and are likely to be pathogenic, with treatment aimed at antibody-depleting agents often with success, while antibodies binding intracellular antigens (e.g., antineuronal nuclear autoantibody type 1 (ANNA1 or anti-Hu)) are a marker of a T-cell-mediated process and treated with T-cell-depleting immunotherapies, with variable responses. Detection and treatment of cancer (when present) are essential. High-dose corticosteroids are the initial treatment in most patients and may serve as a diagnostic test when the diagnosis is uncertain. Repeat cognitive testing after immunotherapy helps document objective improvements. Maintenance immunotherapy is recommended in those at risk for relapse. Prognosis is variable, but paraneoplastic ADE with antibodies to intracellular antigens have a worse prognosis. The field is still developing and future studies should provide guidelines for diagnosis and treatments.

Vitiligo and associated disorders including autoimmune diseases: A prospective study of 200 Indian patients

Background: Vitiligo is commonly associated with autoimmune and nonautoimmune disorders. However, there is a paucity of such data in the Indian context. Aims: We studied common disorders including autoimmune diseases associated with vitiligo. Methods: Clinical details and the results of serological studies comprising anti-TPO and anti-TG antibodies, antiparietal cell antibody, antinuclear antibodies, hepatitis B surface antibody, anti-hepatitis C virus immunoglobulin M antibody, rheumatoid factor, and immunoglobulin E (IgE) levels were analyzed in 200 consecutive vitiligo patients.Results: These 200 (male:female 96:104) patients were aged between 3 and 78 (median age 25) years having vitiligo for 15 days to 60 years. Nonsegmental vitiligo in 192 (96%) patients was the commonly reported pattern. Fifty-three (26.5%) patients had another affected a family member. Clinically, 37 (18.5%) patients had autoimmune disorders and 121 (60.5%) had serological evidence of autoimmunity. Autoimmune thyroid disorders in 85 (42.5%) patients were the most common. Others were rheumatoid arthritis 9 (4.5%), plaque psoriasis 5 (2.5%), alopecia areata 3 (1.5%), and limited cutaneous scleroderma 1 (0.5%). The presence of antithyroglobulin antibody in 53 (26.5%) and antithyroid peroxidase antibody in 44 (22%) patients, rheumatoid factor in 9 (4.5%) patients, and hyper IgE in 75 (37.5%) patients was significant observation. No patient had antiparietal cell antibodies or pernicious anemia. Conclusion: Clinical presentation of our patients conforms to established patterns of vitiligo. Subclinical autoimmune thyroiditis observed in the most cases is indicative of the potential benefit of screening these patients for concurrent thyroid disorders. The association of atopy remains poorly understood. Pernicious anemia and antiparietal cell antibodies do not appear a significant association in our patients.

Serologic evidence of autoimmunity in E2696 and E1694 patients with high-risk melanoma treated with adjuvant interferon alfa

We evaluated Eastern Cooperative Group phase II and III trials E2696 and E1694 to assess the incidence and prognostic significance of autoimmunity induced by adjuvant high-dose interferon-α2b (HDI). In E2696, patients with resectable high-risk melanoma were randomized to receive vaccination with GM2-KLH/QS-1 (GMK) plus concurrent HDI, GMK plus sequential HDI, or GMK alone. E1694 randomized patients to either HDI or GMK. Sera from 103 patients in E2696 and 691 patients in E1694 banked at baseline and up to three subsequent time points were tested by ELISA for the development of five autoantibodies. In E2696, autoantibodies were induced in 16 patients (23.2%; n=69) receiving HDI and GMK and two patients (5.9%; n=34) receiving GMK alone (P=0.031). Of 691 patients in E1694, 67 (19.1%) who received HDI (n=350) developed autoantibodies, but only 16 patients (4.7%) developed autoantibodies in the vaccine group (n=341; P<0.001). Almost all induced autoantibodies were detected at ≥12 weeks after the initiation of therapy. A 1-year landmark analysis among resected stage III patients treated with HDI in E1694 showed a trend toward a survival advantage associated with HDI-induced autoimmunity (hazard ratio=0.80; 95% confidence interval: 0.50-1.98; P=0.33). Therefore, adjuvant HDI therapy is associated with the induction of autoimmunity that should be further investigated prospectively as a surrogate marker of adjuvant therapeutic benefit. This potential biomarker develops over the course of up to 1 year, and cannot be used to alter the course of therapy. Studies of the genetic determinants of this response may better discriminate patients more likely to benefit from HDI immunomodulatory therapy.

Plasma cell hepatitis in liver allografts: Variant of rejection or autoimmune hepatitis?

Plasma cell hepatitis in liver allografts: Variant of rejection or autoimmune hepatitis?

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。

Lupus‐like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p

Systemic lupus erythematosus (SLE) is associated with type I interferons (IFNs) and can be induced by IFNalpha treatment. This study looked for evidence of autoimmunity in a pedigree consisting of 4 family members with a balanced translocation 9;21 and 2 members with an unbalanced translocation resulting in trisomy of the short (p) arm and part of the long (q) arm of chromosome 9. These latter 2 subjects had 3 copies of the IFN gene cluster. Subjects were evaluated clinically and serologically for autoimmune disease. Expression levels of IFNalpha4, IFNbeta, the type I IFN-inducible gene Mx1, the type I IFN receptor, interleukin-6, and tumor necrosis factor alpha were determined by real-time polymerase chain reaction. Circulating plasmacytoid dendritic cells, the main IFN-producing cells, were quantified by flow cytometry. Both subjects with trisomy of chromosome 9p had a lupus-like syndrome with joint manifestations and antinuclear antibodies: one had anti-RNP and antiphospholipid autoantibodies, and the other had anti-Ro 60. The 3 family members with a balanced translocation 9;21 had no clinical or serologic evidence of autoimmunity, similar to that in relatives who were unaffected by the chromosomal translocation. In the 2 subjects with trisomy of 9p, high levels of IFNalpha/beta (comparable with those found in patients with SLE), increased signaling through the IFN receptor (as indicated by high Mx1 expression), and low levels of circulating plasmacytoid dendritic cells (as observed in patients with SLE) were evident. These abnormalities were not seen in individuals with a balanced translocation. Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFNalpha/beta and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE.

Diagnosis and definition of primary Sjögren's syndrome

During the last years, several sets of criteria for the diagnosis and classification of primary Sjo¨gren's syndrome (SS) have been promulgated. So far none has achieved universal acceptance. It is conceivable that the lack of pathognomonic features of SS and the frequent coexistence of SS with other connective tissue di-seases partly explain the lack of agreement. Regardless of criteria preference the final diagnosis of SS should reflect the definition of the syndrome, being an inflammatory and autoimmune rheumatic disease. It is therefore suggested that any criteria employed should include a mandatory combination of measurements of exocrine dysfunction, histological confirmation of inflammation, serological evidence of autoimmunity and exclusion of diseases mimicking primary Sjo¨gren's syndrome.

Pulmonary veno-occlusive disease presenting with thrombosis of pulmonary arteries.

Pulmonary veno-occlusive disease is a rare cause of pulmonary hypertension. An unusual case presenting with thrombosis of the right pulmonary artery and serological evidence of autoimmunity is reported.

TRANSIENT NEONATAL DIABETES MELLITUS (TNDM) AND SUBSEQUENT (10 yr later) PERRANENT IDDM UNRELATED TO AUTOIMMUNITY

We describe the sixth case reported until now of permanent diabetes not associated with serological evidence of autoimmunity in a child who developed INDM 10 yr earlier. A small for gestational age infant developed hyperglycemia at 25 days of age and required insulin therapy for the first 9 mo of life. During a 10 yr longitudinal follow-up, ICA, IAA and organ specific and non-specific autoantibodies were negative, but sequential IVGII showed a first phase insulin reponse (FPIR) < 1st centile (15-28) uU/ml) and mean HbA1c value was 6.1 ± 0.8%. Transient hyperglycemia and glucosuria were recorde at age 4 and 6.3 yr during and intercurrent illness. HLA type was DR2. At age 10 yr & 1 mo (Tanner stage 1-2)a progressive blood glucose increase was observed from 4 to 7 a.m. with a spontaneous normalisation before noon. FPIR was 12 uU/ml). Six isophane insulin units injected at 10 p.m. prevented glycemia increase. Six mo latter (FPIR = 18 uU/ml; ICA & IAA negative) & permanent insulin treatment was started. During 3 yr period preceding insulin therapy, a progressive decrease in growth velocity was observed with high stimulated GH and low IGF1 levels. With insulin therapy (0.51 ± 0.15 U/kg/day) a catch-up growth and a normalization of IGF1 were obtained. The physiological increase in insulin resistance during puberty could be at the origin of (definitive?) insulin dependence in this subject.

Production of autoantibodies to cellular antigens by human B cells transformed by Epstein-Barr virus

Lymphocytes obtained from the blood of three patients who lacked clinical and serologic evidence of autoimmunity were inoculated with Epstein-Barr virus (EBV) and plated in microwell cultures at low cell densities. Large numbers of the resulting transformed cell lines produced IgM autoantibodies which reacted by ELISA with antigens in cultured human fibroblasts. Precursor frequencies of autoantibody-secreting transformed cells ranged from 27 to 630 per 10 6 cells. Autoantibodies from 20 ELISA-positive cell lines were studied by indirect immunofluorescence and found to react with a variety of highly conserved cellular antigens. Eleven cell lines were tested for the production of multiple isotypes; six of these cell lines produced both IgM and IgG autoantibodies. Findings point to the existence in normal human beings of a sizable population of B cells committed to synthesize a broad spectrum of autoantibodies and demonstrate that EBV transformation provides a potent tool for exploring the normal human B-cell repertoire.

Prospective study of immunologic effects of hydralazine in hypertensive patients

Twenty-seven hypertensive patients (23 of whom were black) were treated with hydralazine as their major antihypertensive drug and were followed for evidence of autoimmunity and clinical systemic lupus erythematosus (SLE). Only one patient developed SLE but many, although asymptomatic, had serologic evidence of autoimmunity: antibodies to single- and double-stranded ribonucleic acid (RNA), single-stranded deoxyribonucleic acid (DNA), histones, and lymphocytes. Acetylation phenotype profoundly influenced this response; slow acetylators had a higher incidence and larger amounts of autoantibodies. Antibodies to both types of RNA were a more sensitive index of autoimmunity than antinuclear antibodies. Hydralazine treatment did not alter cell-mediated immune responses. The hydralazine SLE patient had large amounts of autoantibodies that were predominantly IgG, while in the others IgM autoantibodies were predominant. No antibodies, but positive lymphoproliferative responses to hydralazine, were found in half the patients tested.

Autoimmunity induced by syngeneic splenocyte membranes carrying irreversibly adsorbed paramyxovirus.

Newcastle disease virus was adsorbed to a membrane fraction prepared from splenocytes, and the resulting preparation was injected into syngeneic C3H mice. Complement fixing and cytotoxic antibodies reactive with syngeneic tissue and intact cells developed, and some mice died with autoimmune disease characterized by wasting, severe kidney damage, and loss of lymphoid tissue as described previously for animals receiving the membrane fraction of a syngeneic lymphoma in which Newcastle disease virus had grown. Similar experiments were done with L929 mouse fibroblasts and allogeneic spleen membrane fractions. With syngeneic spleen tissue and L929 fibroblasts, serological evidence of autoimmunity appeared after several injections, but deaths from autoimmunity were considerably delayed unless Freund's complete adjuvant was given with the antigen. The results suggest that antigen modification occurs after adsorption of the paramyxovirus to normal tissue as well as lymphoma cell membranes.

The iceberg analogy of autoimmunity.

IMPORTANT contributions to the understanding of autoimmune processes have come from studies on populations (Serafini, Torrigiani & Masala, 1964; Jacobs et aL, 1969; Whittingham et al., 1969a; Couchman, Wigley & Prior, 1970; Hooper et al., 1971) which have shown a substantial proportion of subjects, usually elderly, with serological stigmata of autoimmunity. The iceberg analogy of autoimmunity is applicable in this context in that what is seen above the surface of the sea is only a small part of the total mass of the iceberg, corresponding to that relatively small number ofpatients with symptomatic autoimmune disease in the entire population. In the figure the iceberg represents the total population. The man in the boat is the clinician who sees as the top of the iceberg those patients with symptomatic autoimmune disease (clin AID) to which he ascribes a clinical diagnosis. The snorkeldiver is the histopathologist who, by viewing the iceberg from the surface or by making a shallow dive below the surface sees the same diseases as the clinician and, in addition, histologically evident but clinically insignificant autoimmune lesions (subclin AID). These are the mild non-destructive, focal inflammatory changes of gastritis, thyroiditis and sialadenitis seen in random histological surveys of tissues available by biopsy (Edwards & Coghill, 1966) or at necropsy (Waterhouse & Doniach, 1966; Bastenie et al., 1967). The aqualung diver is the serologist who by diving deeper below the surface sees serological evidence of autoimmunity (serolog AID) in an even larger proportion of the population with and without symptomatic autoimmune disease; the results of the population surveys indicate that this is a substantial portion of the iceberg. The 'unseen', the lowest portion of the iceberg, represents that remaining segment of the population, mostly young and mostly healthy, in whom stigmata of autoimmunity have not as yet appeared or will never appear. The sun beating down on the exposed top of the iceberg causes it to melt, and this in our analogy represents the various environmental agents which