Autoimmune Phenomena Research Articles

Correlation of anti-cardiolipin antibodies with right ventricular systolic strain in systemic lupus erythematosus patients

IntroductionThe association between anticardiolipin antibodies (aCL) and cardiac disease in the presence of systemic lupus erythematosus (SLE) has been reported in various clinical trials. However, the correlation between these auto-antibodies and right ventricular (RV) function has been inadequately investigated. ObjectiveThe present study investigated the possible correlation of the plasma anticardiolipin antibodies, as a marker of autoimmune phenomenon, with RV functions, assessed by right ventricular speckle tracking, in patients with systemic lupus erythematosus independent of significant pulmonary hypertension, systolic dysfunction or valvular disease. MethodsForty-six SLE patients and 20 healthy controls were enrolled in our study and submitted thorough history, complete clinical examination then clinical scoring according to SLEDAI-2K score and then laboratory investigations particularly plasma anticardiolipin Ig_G or Ig_M antibodies. Then echocardiography was done to assess cardiac dimensions, left ventricular systolic functions, right ventricular functions and lastly speckle tracking for assessment of the right ventricular systolic strain. ResultsMost of the study patients were young adult females with long-standing SLE (mean=26±3.1). All study patients had a high clinical SLE score (>6). All patients were normotensives and non-diabetics. No significant correlation was found between anticardiolipin titre and left ventricular dimensions or systolic functions. Significant negative correlation was found between RV strain and plasma level of both anticardiolipin Ig_M and Ig_G. ConclusionThe present study identified that with the use of 2D speckle tracking in patients with SLE, right ventricular systolic function was significantly diminished with rising plasma titre of autoimmune (Ig_G or Ig_M) antibodies independent of cardiovascular risk factors.

Insight into pathogenesis of Sjögren's syndrome: Dissection on autoimmune infiltrates and epithelial cells

Sjögren's syndrome (SS) is a chronic autoimmune disease with broad clinical spectrum, extending from benign exocrinopathy to severe systemic disease and lymphoma development. The glandular and extraglandular dysfunction of SS is associated with lymphocytic infiltrates that invade the epithelial structures of affected organs. The in-depth study of autoimmune lesions in the minor salivary glands (MSG), which are the major target-organ of SS responses, revealed that the lymphocytic infiltrates vary in severity and composition among SS-patients, are full-blown at diagnosis and remain unchanged thereafter. Although the pathogenetic pathways underlying SS have not yet elucidated, it is well-established that glandular epithelial cells are central regulators of local autoimmune responses. Moreover, chronic inflammation affects epithelial function and phenotype, which strengthens or weakens their immunoregulatory/secretory function, leading to deterioration of autoimmune phenomena. Herein, the current findings regarding the autoimmune lesions, the role of epithelial cells and their interaction with infiltrating lymphocytic cells are discussed.

Vaccination and Autoimmune Phenomena

The purpose of this review is to provide an up-to-date outlook on autoimmune phenomena associated with vaccination. Autoimmune reactions triggered by vaccination are a rare occurrence, but a frequent cause of concern. Search of available medical literature for terms “vaccination” and “autoimmunity” or “autoimmune” was performed. Additional articles were indentified based on citations in retrieved articles. Initiation of an autoimmune response by vaccination is possible, but rare. Potential mechanisms include molecular mimicry and bystander activation. In addition, adjuvants present in vaccines may trigger an autoimmune response in specifically predisposed persons by stimulating innate immunity. Documented instances of vaccine-related autoimmunity include Guillain-Barre syndrome following 1976 pandemic influenza (New Jersey strain) vaccine, immune thrombocytopenic purpura triggered by measles, mumps and rubella (MMR) vaccine, and myopericarditis associated with smallpox vaccine. Many autoimmune phenomena have been reported to have occurred in individual patients, or series of patients, in temporal association with the administration of a vaccine. However, controlled studies in most such instances either failed to confirm a causal relationship or were not performed. Conclusion – The weight of currently available evidence supports the conclusion that any risks of autoimmune reactions to vaccines are far outweighed by vaccine-afforded protection against infections, particularly in view of the fact that infections, including vaccine-preventable infections, are most important triggers of autoimmunity. However, research into autoimmune reactions apparently initiated by vaccines is potentially of great importance in the continuing quest to improve scientific understanding of how the immune system functions in health and disease, as well as to widen the evidence base for future efforts directed toward additional improvement in vaccine safety.

Immediate transient thrombocytopenia at the time of alemtuzumab infusion in multiple sclerosis

Background: Alemtuzumab is a monoclonal antibody approved for relapsing-remitting multiple sclerosis (RRMS). Although Immune thrombocytopenia (ITP) has been reported as a secondary autoimmune phenomenon following alemtuzumab infusion, immediate thrombocytopenia during the infusion has not been reported. Objective: We report transient, reversible, self-limiting acute-onset thrombocytopenia during the first course with alemtuzumab. Results and conclusion: In total, 3 of 22 paitents developed mild self-limited bruising associated with a drop in platelet count from their baseline during the intial 5-day course of alemtuzumab. Upon chart review, all 22 patients who received alemtuzumab developed an immediate mostly asymptomatic drop in platelet count which returned to normal within 2 months post-infusion.

Retrospective study comparing survival when ipilimimab used with and without radiotherapy in patients with advanced melanoma.

83 Background: Ipilimumab, a monoclonal antibody targeting CTLA-4, has increased median survival in patients with advanced melanoma from 6.4 to 10 months, with 20% of patients showing a sustained response. Preclinical and clinical studies have shown possible synergistic and abscopal effects between ipilimumab and radiotherapy. The aim of this study was to compare survival curves of patients who have received ipilimumab with and without radiotherapy, and also look at other potential prognostic indicators for patients with advanced melanoma. Methods: Data was collected retrospectively from patients with advanced melanoma treated with ipilimumab at Royal Cornwall Hospital (RCH), United Kingdom. The data collection proforma included: demographic details, BRAF status, treatments prior to and since ipilimumab, whether and when radiotherapy given, response, autoimmune phenomena documented, overall survival, and survival time since ipilimumab. Results: 43 patients (20 men and 23 women) have received ipilimumab for metastatic melanoma at RCH between 2011 and 2015. Age range 27-88 years, with a median age of 60 years. 13 were BRAF mutated, 28 were BRAF wild-type and 2 were unknown. 33% of patients who received ipilimumab had some response to it, with 21% achieving a complete response. 25% of patient who displayed autoimmune phenomena clinically responded to ipilimumab; only 15% of those who did not display autoimmune phenomena clinically responded. 20 patients received radiotherapy and 23 did not; there was no significant survival difference related to radiotherapy usage. Patients with the BRAF mutation had a shorter median survival than those who were BRAF wild-type. Conclusions: Although this study was retrospective and not randomised, it appears to show an increased likelihood of a response to ipilimumab in patients who also had autoimmune side effects from treatment. Patients with a BRAF mutation had a shorter median survival than those who were BRAF wild type. The addition of radiotherapy to ipilimumab did not appear to impact on survival or response, although, as the patients were not randomised as to whether they received radiotherapy it is difficult to draw firm conclusions from this.

Lipophagic Panniculitis of Childhood: A Case Report and Comprehensive Review of the Literature

Lipophagic panniculitis of childhood is a rare condition notable clinically for an inflammatory panniculitis followed by the development of permanent lipoatrophy. In this regard, the term lipoatrophic panniculitis has been used synonymously with lipophagic panniculitis. Additional designations include lipophagic lipoatrophic panniculitis and annular lipoatrophic panniculitis of the ankles. Although lipophagic panniculitis has been associated with a number of autoimmune phenomena, a paucity of reports and limited pathological analyses to date renders this disease an elusive one whose pathogenesis is not yet established. We describe the clinical, histopathologic, and immunohistochemical findings in a case of lipophagic panniculitis of childhood in a 7-year-old boy and present it in the context of a comprehensive review of the literature. Furthermore, we offer a hypothesis regarding the pathogenetic basis of lipophagic panniculitis of childhood, suggesting cellular immunity targeting the adipocyte at the crux of its pathogenesis.

Vaccine Induced Acute Transverse Myelitis: Case Report

Acute transverse myelitis is a focal inflammatory disorder of the spinal cord [1]. One of the main etiologic factors include, multiple sclerosis, post-infectious and post-traumatic events although autoimmune phenomenon is the most common cause [2].Transverse Myelitis (TM) due to etiology other than Multiple Sclerosis has shown spinal cord involvement of two or more segments [3]. Annually millions of active immunization with vaccines is carried out globally with little transverse myelitis caused because of the adverse reactions due to these vaccinations [4,5]. In order to improve accuracy of reporting, research and diagnosis, the Transverse Myelitis Consortium Working Group (TMCWG) has produced criteria for the diagnosis of ATM [6].Here we report a case of TM in adult, diagnosed as TM consistent with the TMCWG criteria and probably this is the first ever been reported case from Nepal.

Clinical Determinants of Durable Clinical Benefit of Pembrolizumab in Veterans With Advanced Non–Small-Cell Lung Cancer

BackgroundBecause of the prevalence of smoking in the veteran population, non–small-cell lung cancer (NSCLC) remains a significant cause of morbidity and mortality. The objectives of our study were to evaluate the extent of durable clinical benefit (DCB) to pembrolizumab in veterans with metastatic NSCLC and to identify clinical determinants of DCB. Materials and MethodsProspective clinical data on veterans receiving pembrolizumab were collected. Duration of response was calculated from the first date of infusion until date of disease progression on computed tomography scans, defined according to Response Evaluation Criteria in Solid Tumors version 1.1 (CTCAE). ResultsAs of the censor date, 25 veterans consented and 24 were evaluable. The response rate was 25% (6 of 24 patients), with all achieving a partial response. Four patients received palliative radiation because of focal progression and continued to receive pembrolizumab, leading to a DCB rate of 41% (10 of 24 patients). The mean duration of response at the censor date was 12.9 months (95% confidence interval [CI], 9.9-15.9) and 2.7 months (95% CI, 1.9-4.3) for those with and without DCB, respectively. Patients without DCB had a higher pack-year smoking history (P = .007). An increase in peripheral blood absolute lymphocyte count (ALC) during therapy was seen in patients with DCB (P = .073). There were no CTCAE Grade > 3 adverse events. All immune-related adverse events occurred in patients with DCB. ConclusionNearly half of the veterans exhibited DCB and pembrolizumab therapy was well tolerated. An increase in ALC from baseline and occurrence of autoimmune phenomena might be associated with DCB. Immunotherapy with pembrolizumab is a promising therapeutic strategy in veterans with advanced NSCLC.

P617 Extraintestinal autoimmune phenomena during treatment with vedolizumab

P617 Extraintestinal autoimmune phenomena during treatment with vedolizumab

Relationship between Autoimmune Diseases and Imbalances in Helper/Suppressor T-cell Populations after Rituximab-containing Chemotherapyfor Non-Hodgkin Lymphoma

Immunologic abnormalities including autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) have been described in patients with non-Hodgkin lymphoma. In some cases, anti-red cell or platelet antibodies are produced by lymphoma cells. However, cases of the occurrence of autoimmune diseases without recurrence of lymphomas have been also reported. The relationship between autoimmune diseases with post-bone marrow transplantation and Hodgkin disease may be attributed to immune dysfunctions, particularly those involving T cells. This autoimmune phenomenon may be related to imbalances in helper/suppressor T-cell populations. Imbalances in helper and suppressor T-cell populations have been reported after R-CHOP chemotherapy, and the recovery of serum IgG and CD4+ counts was observed more than 2 years after R-CHOP therapy in patients with B-cell lymphoma. In this report, we present a case of an 87-year-old man who was treated with rituximab-containing chemotherapy and maintained complete remission. However, the immunophenotyping of peripheral blood and bone mallow mononuclear cells revealed a reversed CD4/CD8 ratio. Two years later, he developed ITP. He was treated with intravenous immunoglobulin and eltrobopag, and thrombocytopenia improved. Five years later, he developed pneumonia and sudden Coombs-positive hemolytic anemia caused by autoantibodies against D antigen and thrombocytopenia without the recurrence of lymphoma. He was treated with prednisolone and a pulse dose of methylprednisolone; however, his response to therapy was poor and he subsequently died. We herein report a case who have been showed reversed imbalances in the helper/suppressor T cell populations over 2 years after R-CHOP therapy, developed AIHA and ITP without recurrence of lymphoma. The long-term monitoring of T-cell counts after rituximab containing chemotherapies is important, and careful attention to infection signs.

Chagas disease-associated kidney injury – A review

BackgroundChagas’ disease is caused by the protozoa Trypanosoma cruzi, in which kidney injury is rarely described. The aim of this study is to describe the features of kidney injury in Chagas’ disease. MethodsThis is a review study regarding kidney injury associated with Chagas disease. A deep search was performed in the main medical databases (PubMed and Scielo), using the key words “Chagas disease” and “Kidney”. ResultsRenal involvement is a rare manifestation of Chagas’ disease, and there are few studies on the subject in literature. There is evidence of functional and structural renal alterations after T. cruzi infection. The occurrence of glomerulonephritis in the chronic phase of the disease has been reported in infections by T. cruzi. The pathphysiology of renal involvement in Chagas’ disease seems to include autoimmune phenomena. T. cruzi antigens have also been identified in renal graft glomeruli and interstitium in a patient with acute form of the Chagas’ disease. The most common lesions associated with the trypanosomes are mesangial proliferative glomerulonephritis and membranoproliferative glomerulonephritis. The specific treatment aims to cure the infection, prevent organ lesions or their progress and decrease the possibility of T. cruzi transmission, being effective in most cases. ConclusionRenal function deterioration is observed in patients with Chagas’ disease, but there is no currently consistent data demonstrating renal function recovery after specific treatment. Further studies are required to better investigate renal involvement in Chagas’ disease.

Recombinant Interferon Alpha-2b is a High-Affinity Antigen for Type 1 Diabetes Autoantibodies.

Type 1 diabetes results from T-cell-mediated destruction of the beta cells of the pancreas and is associated with several autoimmune phenomena. Many studies have suggested the involvement of interferon alpha (IFN α) in the development of type 1 diabetes, but the exact mechanism remains unclear. In this study, the binding of type 1 diabetes antibodies with recombinant interferon alpha-2b (hrIFN α-2b), their gene (cIFN α-2b gene) and commercially available interferon α-2b (IFN α-2b) were assessed. Furthermore, we also sought to use anti-hrIFN α-2b antibodies as a probe for the estimation of plasma IFN α in patients with type 1 diabetes. The binding specificity of antibodies was analyzed by direct binding, inhibition ELISA and quantitative precipitin titration in 45 patients with type 1 diabetes and 30 control subjects. Competition ELISA was also used to estimate INF α in the serum of patients with type 1 diabetes. Antibodies from type 1 diabetes sera, purified in a protein A-agarose matrix, exhibited greater recognition of hrIFN α-2b than IFN α-2b (p<0.05) and cIFN α-2b gene (p<0.001). The relative affinity of type 1 diabetes antibodies for the hrIFN α-2b, IFN α-2b and cIFN α-2b genes was found to be 1.34×10-7, 1.28×10-6 and 1.13×10-6, respectively. The concentration of plasma INF α evaluated by induced antibodies was found to be significantly higher than in controls (p<0.05). High binding of hrIFN α-2b with IgG from patients with type 1 diabetes might suggest involvement of hrIFN α-2b in type 1 diabetes, especially as an antigenic agent. Anti-hrIFN α-2b antibodies were shown to be good probes for estimation of plasma INF α in patients with type 1 diabetes.

Prevalence of Autoantibodies in Healthy Adults in Pakistani Population

Introduction: Autoimmune phenomenon is attributed to a number of diseases which were once considered idiopathic. In humans, production of auto antibodies (a-Abs) against self-antigens is quite frequent but earlier their presence was associated with autoimmune diseases, however a-Abs have been documented in non-autoimmune disorders i.e. complicated pregnancy, cancer, stroke etc. In Pakistan, limited data is available on frequency of a-Abs, therefore this study was designed to determine serum level of antinuclear antibody (ANA), Rheumatoid factor (RF) and anti dsDNA antibodies in apparently healthy population.Materials and methods: After written informed consent, blood sample of 256 subjects was obtained by random sampling. Participants of established autoimmune diseases were excluded. Enzyme linked immunosorbent assay (ELISA) was used to determine ANA, RF and anti-dsDNA antibody. Categorical variables were compared by using c2 test. A p value &lt;0.05 was considered statistically significant.Results: Rheumatoid factor was the most frequent a-Ab (18%), followed by anti dsDNA (7.4%), while ANA was the lowest (0.4%) antibody detected. Only RF had a statistically significant association with gender (p=0.047). No association of these antibodies with age was detected.Conclusion: Rheumatoid factor auto antibody was more prevalent as compared to ANA and dsDNA antibody in healthy adults.Bangladesh Journal of Medical Science Vol.15(4) 2016 p.579-582

Four Cases of Lenalidomide-Associated Immune Thrombocytopenia

IntroductionHematologic neoplasms are associated with an increased incidence of autoimmune events, particularly evident in non‐Hodgkin lymphomas (NHL) and especially chronic lymphocytic leukemia (CLL); until now only few cases have been described in patients affected by multiple myeloma (MM) and other plasma cell disorders. The introduction of new drugs, in particular immunomodulatory drugs (IMiDs), could increase the risk of these complications.Herein we describe four cases of immune thrombocytopenia (ITP) occurred during Lenalidomide (LEN) therapy in 3 patients affected by MM and 1 with light‐chain amyloidosis.Case reportsCase 1. A 66‐year old woman with relapsed IgGk MM started 2th line treatment with LEN/DEX 25 mg/d-20 mg/w. During the first 5 cycles she presented moderate hematologic toxicity which resolved after dose reduction (LEN 15 mg/d). A severe and isolated thrombocytopenia appeared after 5th cycle with patient in good partial remission (PR) for MM. A bone marrow evaluation showed absence of plasma cells and abundant megakaryocytes leading to a diagnosis of ITP. LEN was interrupted and steroid therapy (prednisone 1 mg/Kg) and IV Ig infusion administered, obtaining a transient good response (from 17 to 114 x 109/l). LEN was then restarted at lower dosage but a month after, while myeloma still was in good response, ITP relapsed complicated by intracranial hemorrhage and was successfully treated with IV Ig; Len was definitely interrupted. At the third relapse Rituximab (750 mg/w x 4 weeks) was administered with only minimal increase of platelet count (Fig 1). Afterwards, the patient died due to rapid MM progression.Case 2. A 76‐year old woman with relapsed IgGλ MM started 2th line treatment with LEN 15 mg. After the 3rd cycle, having obtained a very good partial remission (VGPR), she presented with grade 3 thrombocytopenia which did not ameliorate with LEN suspension and resolved only after introduction of steroid, thus supporting ITP diagnosis. She underwent a 4th cycle of LEN/DEX maintaining a normal platelet count but then LEN was interrupted due to rapid MM progression. (Fig 2).Case 3. A 78‐year old woman with renal amyloidosis in IgAλ gammopathy started a 2nd line treatment with LEN/DEX 15 mg/d-20 mg/w with a significant reduction in proteinuria. During the 6th cycle she presented with diffuse purpura and a platelet count of 18x109/L. She received platelet transfusion and bone marrow evaluation showed abundant megakaryocytes supporting the diagnosis of ITP. Furthermore anti‐platelet antibodies search resulted positive. Steroid therapy was started with partial response on platelet count but the patient remained steroid‐therapy dependent.Case 4. A 66‐year‐old woman affected by MM started a 2th‐line treatment with LEN‐DEX 25 mg/d-20 mg/w. After the third cycle, being the patient in PR, a isolated grade 3 thrombocytopenia developed, persisting despite discontinuation of LEN. Viral infections were excluded and antiplatelet antibodies search resulted positive. Therefore she started steroid therapy (prednisone 1 mg/Kg) with an progressive increase of platelet count from 44 to 80x109/L after a month of therapy, that is ongoing. Lenalidomide has not yet been restarted.DiscussionWe report four cases of ITP developing during LEN therapy with the characteristics of ITP. None of these patients had a history of previous autoimmune events, the decline of platelet count was rapid and other causes of thrombocytopenia were excluded or unlikely in all the cases. Furthermore diagnosis was supported by consistent bone marrow evaluation in two cases. Considering the temporal association in these four cases, the ITP mechanism may be related to the immunomodulation and T‐cell activation caused by LEN.Even if further other studies are needed, it seems reasonable to consider a possible association between LEN and autoimmune phenomena, in particular ITP. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Indolent Phenotype of RAS-Associated Autoimmune Leukoproliferative Disorder (RALD) Is Characterized By Single Somatic Mutations in RAS Genes with Absence of Cooperating Mutations

RAS-Associated Autoimmune Leukoproliferative Disorder (RALD) is a chronic indolent condition that typically presents in childhood with monocytosis, lymphocytosis, autoimmune phenomena, splenomegaly, and variable lymphadenopathy. RALD is characterized by somatic mutations in KRAS or NRAS in hematopoietic cells (myeloid and lymphoid), resulting in missense mutations involving the 12th or 13thcodon. Despite the indolent course of RALD, it shares some overlapping clinical features and similar genetic defects with Juvenile Myelomonocytic Leukemia (JMML), which is characterized by canonical and non-canonical RAS-pathway mutations. All RALD patients have normal bone marrow karyotypes. While patients with JMML often harbor monosomy 7 or other karyotypic abnormalities, normal karyotypes are also not uncommon in JMML. Optimal therapeutic management of RALD and JMML differs significantly, necessitating accurate diagnostic discrimination of RALD and normal karyotype JMML.Recent JMML studies have characterized the genomic landscape of JMML, which involves additional recurrent mutations that are thought to cooperate with RAS-pathway mutations driving the malignant phenotype of JMML. We sought to evaluate the genomic landscape of RALD for the presence of non-RAS cooperating mutations reported in JMML.Using targeted sequencing for 54 genes associated with myeloid malignancies, amplicon libraries were constructed from peripheral blood mononuclear cells (PBMCs) collected from 11 patients diagnosed with RALD (6 with previously identified KRAS and 5 with previously identified NRAS mutations) and sequenced with an average read depth of ~3000x. Variants were identified using the Illumina miSeq reporter software and analyzed using Illumina Variant Studio. Variants were filtered based SIFT, PolyPhen, and CADD predictions, ClinVar annotations, and mutations previously identified in JMML. Over 90% of the mutated genes reported in JMML sequencing reports, were evaluated (including KRAS, NRAS, CBL, PTPN11, SH2B3, SETBP1, GATA2, RUNX1, ASXL1, EZH2, DNMT3A, and ZRSR2). Of note, only the KRAS or NRAS mutations, initially identified from Sanger sequencing, were identified as disease-contributing and no other known pathogenic mutations were detected in the RALD cohort. Variant allele frequencies (VAFs) of KRAS and NRAS mutations in RALD ranged from 32.3%-50.8% with a median VAF of 46.6%. In order to further investigate genes not included in the targeted sequencing panel that may be contributing to disease, whole exome sequencing (WES) was performed on PBMCs from 7 RALD patients (4 KRAS patients, 3 NRAS patients). Despite the expanded genomic sequencing in WES (mean coverage of 225x), only the single pathogenic KRAS or NRAS mutation, known to be disease-related, was identified. No other mutations that were previously identified in JMML were detected in the WES data set. Based on presence of autoimmune phenomena in RALD, a multiplex inflammatory cytokine immunoassay investigating GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, and IL-12p70 was used to quantify cytokine levels in the plasma of 9 RALD patients and 17 healthy volunteers. The levels of IL-2, IL-6, and IL-10 were found significantly increased in RALD patients. IL-2 was 4.6 fold higher in RALD than controls (median 0.696 pg/mL vs. 0.149 pg/mL; p=0.049). Similarly, IL-6 was 10 fold higher in RALD than controls (median 6.42 pg/mL vs. 0.63 pg/mL; p=0.035), and IL-10 was 18 fold higher in RALD than controls (median 26.9 pg/mL vs. 1.49 pg/mL; p=0.018).Overall, these findings provide evidence that RALD, in our patient cohort with an indolent clinical course, is characterized by single somatic KRAS or NRAS mutations with the absence of cytogenetic abnormalities and cooperating mutations that are associated with malignancy. This suggests that in the spectrum of so-called RASopathies, RALD represents a non-malignant proliferative hematopoietic disease that is clinically distinct from JMML. The altered plasma cytokine profile in RALD may play a role in the autoimmune features of the disease and be related to sustained activation of the RAS pathway in hematopoietic cells. Further investigation is imperative to distinguish these two overlapping entities characterized by RAS pathway mutations, and to better understand the spectrum of disease from indolence to aggressive malignancy. DisclosuresNo relevant conflicts of interest to declare.

Subset-Specific Recurrence of Mutations and Identification of Functional Modules Provides New Clues about the Pathogenesis of Large Granular Lymphocyte Leukemia

Background: Large granular lymphocyte (LGL) leukemia is a rare disease characterized by a clonal persistence of cytotoxic T cells or natural killer (NK) cells. Patients usually suffer from cytopenias and other organ-related autoimmune phenomena. These are putatively mediated by the cytotoxic LGL cells constitutively activated following an antigen-driven immune response. In addition to gain-of-function mutations in the STAT3 gene, which occur in 40-50% of patients, recurrent alterations only in the STAT5b and TNFAIP3 tumor suppressor genes have been described thus far. However, based on gene expression analyses, JAK/STAT pathway activation and deregulation of several pro-apoptotic (sphingolipid and FAS/FAS ligand) and pro-survival signaling pathways (PI3K/AKT and RAS) are common features of LGL leukemia.In this project, we aimed to characterize the genomic landscape of LGL leukemia using exome sequencing and systems genetics approaches in a patient cohort including both T- and NK-LGL cases and patients without known STAT mutations.Methods: The study cohort included 19 patients diagnosed with LGL leukemia that underwent exome sequencing analysis with matched germline controls. 13 patients had CD8+ T LGL and 3 patients CD4+ T LGL phenotype and 3 patients were NK LGL cases. From the T LGL leukemia cases CD8+ or CD4+ T cells were sorted (according to the dominant phenotype) and used as the tumor sample. In NK LGL leukemias, sorted CD3neg,CD16/56+ NK cells constituted the tumor fraction that underwent exome sequencing. Polyclonal blood lymphocytes depleted from LGL cells were used as germline controls. The exome was captured with the Nimblegen SeqCap EZ Exome Library v2.0 and the sequencing was performed with the Illumina HiSeq2000 sequencing platform. All bioinformatics steps were carried out using a custom bioinformatics pipeline. Putative somatic variants were identified by subtracting, for each patient, the ones called in the normal samples from those found in the tumor sample. After filtering by call quality and allele frequency in ExAC database, somatic variants were prioritized according to the predicted impact from the SnpEff software. Genes hit by variants putatively altering their function were finally mapped to Kegg and Reactome to generate pathway-derived meta gene networks for the identification of affected functional components.Results: 4 patients had STAT3 mutations and 4 additional cases had STAT5B mutations. In addition to STAT mutations, a number of novel somatic variants, which were recurrently mutated were discovered. These included the tumor suppressor gene FAT4, the epigenetic regulator KMT2D, as well as genes involved in the control of cell proliferation (CDC27 and ARL13B).With the systems genetics approach based on integration of pathway-derived mutated gene network topologies for identification of connected components we were able to discover affected functional modules. The main network component included key genes, which either directly interact (such as the FLT3 tyrosine kinase) or are functionally connected (such as ADCY3, ANGPT2, CD40LG, PRKCD, PTK2, KRAS, and RAB12 genes) with STAT proteins. Additional modules with putative pathogenetic relevance in LGL leukemia and mutated in the absence of STAT mutations were cell cycle control (CDC27, PLK1, CDC25B, RAD21), Notch signaling (NOTCH2, NOTCH3 and MAML3) and epigenetic regulation through histone-lysine methyltransferase activity (KMT2D and ASH1L).The comparison of various LGL leukemia subtypes revealed that the mutation burden was especially high among the CD4+ T LGL leukemia cases. Part of the genes and modules affected were shared between the different subtypes of LGL leukemia, but for example KIR2DL1 mutations were only found in CD8+ and NK LGL leukemia cases.Conclusions: With the exome sequencing and systems genetic approach we were able to discover specific gene networks, which are recurrently mutated in LGL leukemia and particularly in patients without STAT mutations. As several mutated genes are directly or indirectly connected with the STAT pathway, the data strengthen the key role of JAK/STAT signaling in LGL leukemia. The novel identified pathway modules beyond STAT networks provide intriguing insights into the pathobiology of LGL leukemia. DisclosuresMaciejewski:Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Mustjoki:Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Honoraria, Research Funding.

Vaccine Induced Acute Transverse Myelitis: A Case Report

Acute transverse myelitis is a focal infl ammatory disorder of the spinal cord. One of the main etiologic factors include, multiple sclerosis, post-infectious and post-traumatic events although autoimmune phenomenon is the most common cause. Transverse Myelitis (TM) due to etiology other than Multiple Sclerosis has shown spinal cord involvement of two or more segments. Annually millions of active immunization with vaccines is carried out globally with few transverse myelitis caused because of the adverse reactions due to these vaccinations. In order to improve accuracy of reporting, research and diagnosis, the Transverse Myelitis Consortium Working Group (TMCWG) have produced criteria for the diagnosis of ATM. Here we report a case of TM in adult, diagnosed as TM consistent with the TMCWG criteria and probably this is the first ever been reported case from Nepal. Nepal Journal of Neuroscience. Vol. 13, No. 2, 2016, Page: 89-91

Bortezomib-based antibody depletion for refractory autoimmune hematological diseases

AbstractCertain patients with antibody-mediated autoimmune disease exhibit poor responses to conventional immunosuppression, including B-cell depletion with rituximab. Proteasome inhibitors such as bortezomib demonstrate pleiotropic immunomodulatory effects, including direct toxicity to antibody-producing cells. Here, we report preliminary evidence for the efficacy of bortezomib as salvage therapy for refractory autoimmune hematological disease. Thirteen treatment episodes in 10 patients with autoimmune hematological phenomena (autoimmune hemolytic anemia [AIHA; n = 8], acquired hemophilia (n = 1), immune thrombocytopenia (n = 1), and thrombotic thrombocytopenic purpura [TTP; n = 3]) and a median of 5 (range, 3-12) prior lines of therapy demonstrated an overall response rate of 77% (10 of 13) including 38% (5 of 13) complete remissions. The majority of clinical improvements were rapid, correlated with biomarkers of autoantibody reduction, and were associated with an acceptable safety profile. Responses appeared durable following treatment of TTP and acquired hemophilia; AIHA responses were more limited with a pattern of relapse following bortezomib cessation. These data provide proof of concept for the utility of proteasome inhibition as antibody depletion therapy in autoimmune disease.

Inmunodeficiencias primarias

ConceptPrimary immunodeficiencies (PID) are very heterogeneous hereditary diseases, caused mostly by defects in a gene that determine a quantitative and/or qualitative alteration of the immune system and consequently, increased risk of infections by germs encapsulated or opportunistic, autoimmune phenomena or allergy and an increased risk of malignancies. ClassificationThe new classification of PIDs includes 9 groups, based on the phenotype of more than 200 entities. This review will focus on those that affect lymphocytes: antibodies deficiencies and combined immunodeficiencies. DiagnosisThe diagnosis of PIDs should be guided by clinical suspicion, should be performed sequentially and should be based on three simple additional test: blood count, determination of immunoglobulins and study of lymphocyte populations. Finally, the genetic characterization confirms the diagnosis of PID, allows suitable and early treatment and perform genetic counseling.

Pembrolizumab Therapy Triggering an Exacerbation of Preexisting Autoimmune Disease: A Report of 2 Patient Cases.

Historically, metastatic melanoma was uniformly and rapidly lethal, and treatment options were limited. In recent years, however, checkpoint inhibitors have emerged as an accepted standard treatment for patients with advanced melanoma. In clinical trials, these agents have been largely well tolerated and have the potential to result in durable responses. Importantly though, one must recognize the unique side effect profile of these therapies, which can trigger or exacerbate underlying autoimmune disease. Whether this autoimmune activation is associated with a clinical response to therapy has been debated, and while not definitive, there is evidence in the literature of a possible association. The 2 cases presented describe this autoimmune phenomenon, along with a review of the existing literature on the relationship between response to immunotherapy and autoimmune side effects.