Autoimmune Phenomena Research Articles

The high mortality of patients with common variable immunodeficiency and small bowel villous atrophy

Objectives: Common variable immunodeficiency (CVID) is a primary humoral immunodeficiency characterised by reduced serum levels of immunoglobulins, recurrent infections, autoimmune phenomena and lymphoproliferative disorders. Gastrointestinal symptoms are very common in these patients and a coeliac-like villous atrophy was described in some of them. Since mortality in CVID is much higher than in the general population, our aim was to evaluate mortality rates and clinical predictors of survival in patients with both CVID and duodenal villous atrophy.Patients and methods: Sex, date of diagnosis of villous atrophy, HLA genomic typing, date of death/last follow-up, type of complication were retrospectively collected from medical files. Univariate analysis for each predictor was conducted and Kaplan-Meier curves were generated to evaluate survival.Results: Twenty-three patients were enrolled (9 females, mean age at diagnosis of villous atrophy 38 ± 13 years) and 8 of them died after a median time of 96 months (25th–75th 60–120 months) corresponding to a mortality rate of 3.9 per 100 person-years (95% CI 1.9–7.7). Mortality was higher in men compared to women (60 vs. 11/1000 person-years), although not statistically significant. Causes of death included onco-haematological disorders and infections.Conclusions: Although based on a small cohort, our results confirm that patients with CVID and villous atrophy are burdened by a very high mortality mainly due to onco-immunological disorders and infections. Strict follow-up is required in these patients.

A Novel Approach That May Explain the Role of Staphylococcus aureus, Polycations, Neutrophils Pro-Inflammatory Agonists and the Bacteriolysis and Auto Immune Phenomena as Possible Major Events in the Pathogenesis of Atopic Dermatitis: A Working Hypothesis

The aim of the present short communication is to shed a novel light on the auto immune disorder atopic dermatitis by discussing the possible role played by the plethora of toxic agents released by Staphylococcus aureus which can act in a tight synergism with neutrophils derived cationic polyelectrolytes as related to the pathogenesis of atopic dermatitis (AD). This disorder results in inflammation of the skin characterized by itchiness, red skin, a rash, by the accumulations of large numbers of Staphylococcus aureus their toxins and proinflammatory agents secreted by migrating neutrophiles are considered the main cause of AD pathogenicity.

Widespread subacute cutaneous lupus erythematosus in a patient receiving checkpoint inhibitor immunotherapy with ipilimumab and nivolumab

Checkpoint inhibitor immunotherapy, including ipilimumab and nivolumab, is associated with numerous immune-related adverse events including dermatitis, pruritus, hepatitis, diarrhea, and hypophysitis. As the number of patients undergoing immunotherapy treatment increases, however, rare and unusual immune-related adverse events are observed. Many of these resemble known autoimmune phenomenon, such as subacute lupus erythematosus and myositis. Herein, we report a patient with metastatic serous ovarian carcinoma undergoing treatment with combination ipilimumab and nivolumab who developed subacute cutaneous lupus erythematosus (SCLE). Recent case reports have documented SCLE as a novel immune-related adverse event. In our case, she was able to successfully restart immunotherapy after a course of oral corticosteroids and maintenance oral hydroxychloroquine and topical corticosteroid therapy.

Autoimmune/autoinflammatory syndrome induced by adjuvants: what is it and why the controversy?

Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) is a group of autoimmune diseases with possible adjuvant-associated causes, such as siliconosis, macrophagic myofasciitis syndrome, Gulf War syndrome, sick building syndrome, and postvaccination autoimmune phenomena. Over time, an international registry with over 500 patients has been established for this conglomeration of rare syndromes. In spite of this, the very existence of ASIA has been debated at times and the diagnostic criteria have come under criticism. The cause-effect relationship between adjuvants and autoimmune phenomenon is difficult to prove due to lack of precisely defined time range between exposure and disease and also due to numerous exposures to adjuvants a person may have in his or her lifetime. The current article attempts at reviewing the clinical features, diagnostic criteria, and evidence for/against the existence of the disease.

Cutaneous manifestations of angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is a rare form of non-Hodgkin lymphoma often accompanied by autoimmune and paraneoplastic phenomena. Up to 50% of patients with AITL present with skin manifestations. This case series highlights two cases of AITL presenting with unusual cutaneous findings: one with a medium-vessel vasculitis and another with a chronic urticarial eruption. Clinicians should consider AITL in the differential diagnosis of vasculitis or urticaria refractory to standard treatment.

Mechanisms of lymphatic system-specific viral replication and its potential role in autoimmune disease.

Viral infections can be fatal because of the direct cytopathic effects of the virus or the induction of a strong, uncontrolled inflammatory response. Virus and host intrinsic characteristics strongly modulate the outcome of viral infections. Recently we determined the circumstances under which enhanced replication of virus within the lymphoid tissue is beneficial for the outcome of a disease. This enforced viral replication promotes anti-viral immune activation and, counterintuitively, accelerates virus control. In this review we summarize the mechanisms that contribute to enforced viral replication. Antigen-presenting cells and CD169+ macrophages exhibit enforced viral replication after infection with the model viruses lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). Ubiquitin-specific peptidase 18 (Usp18), an endogenous type I interferon blocker in CD169+ macrophages, has been identified as a proviral gene, as are B cell activating factor (BAFF) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Lymphotoxins (LT) strongly enhance viral replication in the spleen and lymph nodes. All these factors modulate splenic architecture and thereby promote the development of CD169+ macrophages. Tumor necrosis factor alpha (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cell signaling (NF-κB) have been found to promote the survival of infected CD169+ macrophages, thereby similarly promoting enforced viral replication. Association of autoimmune disease with infections is evident from (1) autoimmune phenomena described during a chronic virus infection; (2) onset of autoimmune disease simultaneous to viral infections; and (3) experimental evidence. Involvement of virus infection during onset of type I diabetes is strongly evident. Epstein-Bar virus (EBV) infection was discussed to be involved in the pathogenesis of systemic lupus erythematosus. In conclusion, several mechanisms promote viral replication in secondary lymphatic organs. Identifying such factors in humans is a challenge for future studies.

Drug-induced lupus

Drug-induced lupus (DIL) is an autoimmune phenomenon that has similar clinical and laboratory manifestations with idiopathic systemic lupus erythematosus (SLE). About 100 drugs are now known to be associated with the development of DIL. Its diagnosis is verified in the presence of a chronological relationship between the long-term administration of drugs and the mandatory presence of one clinical and one laboratory diagnostic criteria for SLE.The paper deals with the etiology, pathogenesis, and differential diagnosis of DIL. It presents a spectrum of drugs that can cause DIL and considers the features of its different forms.Based on the recent data available in the literature, the authors analyze the occurrence of autoimmune responses due to the useof biologic agents (BAs), primarily tumor necrosis factor-αinhibitors. Therapeutic approaches for DIL are discussed. Recommendations are given for screening the patients in the use of BAs. Clinical examples are provided.

Autoimmune hemolytic anemia, autoimmune neutropenia and aplastic anemia in the elderly

The physiology of the immune system involves morphologic and functional changes occurring along ageing, with a decrease in immune response and an increase in autoimmune phenomena, even in the absence of overt disese. Autoimmune cytopenias, namely autoimmune hemolytic anemia (AIHA), chronic idiopathic neutropenia (CIN) and aplastic anemia (AA), show different epidemiologic predilection, but are increasingly diagnosed in the elderly, where complications and comorbidities are more frequent. A systematic review of recent literature, shows that comorbidities as well as underlying deficiencies, medications, neoplasms, and, pathophysiologic chronic organ failures, frequently challenge the differential diagnosis in this setting and should always be evaluated and excluded. Complications, particularly infections and thrombosis for AIHA, and bleeding for AA, should be monitored and promptly treated. Treatment choice should be carefully weighed on the individual general condition and comorbidities, granted that intense primary care and support (including evidence-based transfusion policies) are provided. Finally, bone marrow histology is highly advisable in the elderly, both at diagnosis to detect underlying conditions, and along the follow-up to monitor possible bone marrow failure or neoplastic evolution.

Non-IgM Secreting Lymphoplasmacytic Lymphoma - Experience of a Reference Center for Waldenstrom Macroglobulinemia

Background: Lymphoplasmacytic lymphoma (LPL) secreting immunoglobulins other than IgM is rare. Therefore, there are very few case series on non-IgM LPL and little is known about the clinical features and outcomes of patients with this disease.Aim: To describe disease characteristics and clinical outcomes of patients with non-IgM LPL.Methods: We identified cases of non-IgM LPL in the records of the Waldenström Macroglobulinemia (WM) clinic at our institute, between the years of 2000-2018. All patients were part of the clinic's registry. We extracted data from their electronic records and included only cases with centrally-confirmed diagnosis. Response assessment was based on 6th IWWM criteria. Time to events was estimated using the Kaplan-Meier method.Results: We found 31 patients with non-IgM LPL. Median age at diagnosis was 63 years (range, 37-83 years), 45% were over the age of 65, and 65% were women. The paraprotein secreted by these tumors was IgG in 20 cases (65%); IgA in 5 (16%), light-chain (LC) in 2 (6%) and was non-secretory (NS) in 4 (13%). Median level of IgG and IgA at diagnosis was 3,967 mg/dl (range, 804-8,006 mh/dl) and 1,980 mg/dl (range, 1,020-6,210 mg/dl), respectively. We included 5 cases with concurrent IgM paraproteinemia, when it was clearly secreted to a lesser extent than dominant immunoglobulin and had similar LC restriction.Five patients had MGUS preceding diagnosis of LPL. Presenting symptoms were anemia-related (n=13), asymptomatic (n=7), neuropathy, autoimmune phenomena, elevated creatinine, bleeding diathesis and recurrent infections (n=3, each). Only 1 patient had B-symptoms. One patient with IgA LPL and serum IgA level of 4,000 mg/dl presented with retinal vein occlusion due to hyperviscosity. Non-bulky (<5 cm) lymphadenopathy was found in 11 patients (35%), and mild splenomegaly in 5 (16%). Anemia was prevalent (53%) with hemoglobin <10 g/dl in 23%. No patient had neutropenia (ANC <1 K/uL) or thrombocytopenia (platelets <100 K/uL) at presentation. Five patients (16%) presented with mild lymphocytosis (median, 7.1 K/uL; range, 3.3-20.6 K/uL). Βeta-2-microglobulin level was >3 mg/L in 48% of available patients (n=12/24).All bone marrow biopsies showed that malignant cells were positive for CD20 and CD19 by flow cytometry; 14% were CD5 positive (subset/dim); 29% CD23 partially-positive; and all were CD10 negative. Five of 19 cases (26%) had cytogenetic abnormalities, but apart from del6q (n=1), none were of commonly known aberrations in hematological malignancies. Only 1 patient with kidney disease underwent renal biopsy that revealed light-chain deposition disease. Amyloidosis was detected in 2 patients, one with neuropathy and the other patient was asymptomatic. The MYD88 L265P mutation was detected in 10 of 14 patients (71%) tested, and CXCR4 mutations in 2 of 8 patients (25%) tested. Both patients with a CXCR4 mutation needed treatment immediately at diagnosis and subsequently had 4 or more lines of therapy.With a median follow up of 4.6 years (95% CI 2.5-7.6 years), 68% of the patients had been treated (n=21), 90% of whom within the first year from diagnosis. As such, the median time to first treatment was 2.3 months. However, time to next therapy was significantly longer, with a median of 4.7 years. Patients had a median of 3 lines of therapy (range, 1-8), including purine analogues in 33% of patients, alkylating agents in 48%, bendamustine in 38%, anti-CD20 monoclonal antibodies in 90%, proteasome inhibitor in 24%, and immunomodulating drugs in 14%. Two patients received ibrutinib: one achieved VGPR with over 3 years remission duration, after prior 7 lines of therapy; and the other, who had only a brief response, was found to carry the CXCR4 mutation. There were 4 (13%) deaths: 1 patient developed Bing-Neel syndrome at first relapse that ultimately lead to his demise; 1 died from treatment complications; and 2 of unknown cause. The 5-year and 10- year OS are 90% (95% CI 64-98%) and 81% (95% CI 49-94%), respectively (Figure 1).Conclusion: To our knowledge, this is the largest reported series of non-IgM LPL and the first to demonstrate excellent long-term outcomes in these patients. [Display omitted] DisclosuresHunter:Pharmacyclics: Consultancy. Treon:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Johnson & Johnson: Consultancy; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Castillo:Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Millennium: Research Funding.

Immune Thrombocytopenia Complications: Implications on Length of Stay and and Mortality

Introduction: Immune thrombocytopenia (ITP) is an autoimmune phenomenon causing increased destruction and insufficient platelet production. ITP can be a healthcare burden due to prolonged treatment (medical and sometimes surgical = splenectomy) required to prevent the relapse and frequent hospitalizations for management of complications such as epistaxis, gastrointestinal bleeding (GIB) or intracranial hemorrhage (ICH). In addition, septicemia and coagulation disorders can occur related to therapy. In this study we analyzed demographics among inpatient admissions with ITP and the variation of length of stay (LOS) and mortality with different complications.Methods: We performed a retrospective cohort analysis of the National Inpatient Sample 2014 Database (HCUP-NIS). Patients were included in the study if they had a primary or secondary diagnosis of ITP and age >18 years. We performed descriptive statistics to characterize the cohort in terms of personal demographic factors (age, race, sex, insurance type, community level income level), hospital characteristics (size, region, teaching status, and urban or rural location). The cohort was classified on based on splenectomy status using procedure diagnosis code. The cohort was further analyzed for complications such as coagulation disorders, GIB, ICH, septicemia and epistaxis using their principal diagnosis. Furthermore, we also looked at the variation in LOS and mortality among them. Univariate and multivariate regression analysis were performed to determine statistical significance. All analyses applied the HCUP-NIS weights.Results: There were 11,535 patients in the cohort. Most were white (64.4%), females (57.95%), and aged < 60 years (55.6%). A significant proportion were covered by Medicare (41.33%). Most care was delivered in large hospitals (55.17%), that were disproportionately urban (94.4%) or teaching (70.61%) institutions. The greatest segment of patients were in the South Atlantic region (20.8%). Epistaxis occurred in 15.3% of patients, GIB in 3.12%, ICH in 0.41%, and septicemia in 0.99%. The mean LOS was 4.73 days (95% CI 4.49 to 4.97). Mean LOS was highest in patients with septicemia (12.3 days), followed by GIB (8.98 days) and ICH (7.99 days), and epistaxis and coagulation disorders (6 days each). LOS was significantly shorter in patients who had undergone splenectomy (AMD -10.67 95% CI-18.32 to -3.03), and longer with septicemia (AMD 9.06 95% CI 1.84 to 16.27). Compared to Medicare, other insurances statuses had shower LOS: uninsured (AMD -6.60 95% CI -10.76 to -1.39), Medicaid (AMD -3.57 95% CI -7.07 to -0.086), and private (AMD -2.67 95% CI -5.39 to 0.037). Risk of death was much higher with GIB (OR 227 95% CI 7.63 to 6757.48, p=0.002) and ICH (OR 100.88 95% CI 10.27 to 990.91, p <0.01).Discussion: Treatment and complications significantly impact LOS and mortality for patients with ITP. Splenectomy is associated with decreased LOS, presumably because of rapid improvement in platelet counts, while septicemia is associated with increased LOS likely related to intensity of service delivered. Insurance types are also independently associated with LOS. It is unclear if this is related to differences in biologic factors (e.g. age, comorbidities, frailty), or process factors (e.g. care management practices, payment incentives). [Display omitted] DisclosuresBussel:Amgen Inc.: Consultancy, Research Funding; Momenta: Consultancy; Prophylix: Consultancy, Research Funding; Protalex: Consultancy; Uptodate: Honoraria; Rigel: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Marks:Lilly: Membership on an entity's Board of Directors or advisory committees; UPMC: Employment; Heron: Membership on an entity's Board of Directors or advisory committees; Odonate: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Equity Ownership.

Evaluation of Combination Tagraxofusp (SL-401) and Hypomethylating Agent (HMA) Therapy for the Treatment of Chronic Myelomonocytic Leukemia (CMML)

Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that is characterized by cytopenias, organomegaly, constitutional symptoms, autoimmune phenomena, and ultimately progression to acute myeloid leukemia (AML). The only known cure for CMML remains allogeneic stem cell transplant. Aside from stem cell transplant, currently utilized therapeutic modalities include hydroxyurea, erythropoietin stimulating agents (ESAs) and hypomethylating agents (HMAs). Azacitidine (AZA) and Decitabine (DAC) have been utilized to treat CMML patients, particularly those with cytopenias, with variable efficacy such that complete response only occurs in a minority of patients. Recent work has identified CD123 (interleukin-3 receptor-α; IL-3R-α) as a potential therapeutic target in myeloid malignancies. CD123 is expressed in a variety of myeloid malignancies, including AML, myelodysplastic syndrome (MDS) and CMML. Further, plasmacytoid dendritic cell infiltrates (pDC) which are known to infiltrate the bone marrow in CMML, express CD123. Tagraxofusp (Elzonris™, SL-401) is a targeted therapy directed to CD123, comprised of recombinant IL-3 fused to a truncated diphtheria toxin payload. Clinical studies of tagraxofusp are being carried out in a variety of hematologic malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), myelofibrosis (MF), and CMML. Data from an ongoing Phase I/II trial of tagraxofusp in relapsed/refractory CMML (n=16 patients) demonstrated spleen size reductions in 100% (8/8) patients with baseline splenomegaly and 2 bone marrow complete responses (BMCRs). Thus, tagraxofusp appears to have single agent clinical activity in CMML. Given this activity, and the known activity of HMAs in CMML, we sought to determine if combination HMA and tagraxofusp may provide added therapeutic utility over HMA therapy alone.Methods: To address this question, we performed preclinical studies using human leukemia cell lines as well as mononuclear cells from primary patient CMML samples. In order to determine active concentrations of both AZA and tagraxofusp in vitro, cell viability assays were performed. K562 cells, which have been previously demonstrated to express CD123, were first studied for sensitivity to AZA and tagraxofusp. The IC50 of AZA was 772uM and 4.8nM for tagraxofusp (Figure 1A). We next performed viability assays using fresh mononuclear cells from CMML patients. The IC50 of single agent AZA was 1442uM, whereas the IC50 of combination AZA and tagraxofusp (at a concentration of 4.8nM) was 725uM. As well, adding tagraxofusp at a concentration of 4.8nM to 1uM AZA in this assay induced a significant reduction in cell viability (Figure 1B; p<0.05). In colony assays, combination AZA and tagraxofusp significantly reduced colony formation when compared to single agent AZA alone (Figure 1 C-E, p<0.05). This effect was observed in samples with a relatively high sensitivity to AZA (Figure 1D) as well as in less sensitive samples (Figure 1E). Addition of AZA to increasing concentrations of tagraxofusp demonstrated a similar significant reduction in colony formation (Figure 1 F, p<0.05). Importantly, a combination effect was observed across samples of different genotypes including patient samples with high risk genotypes, including NRAS/ASXL1/TET2 (Figure 1E) and mutations in SRSF2/TET2/STAG2 (Figure 1C).Conclusions: Current therapeutic options for CMML are limited and CMML remains a significant unmet medical need. Although HMA therapy has demonstrated efficacy in CMML, the effects are often limited in extent and duration. Our preclinical data, including in primary CMML samples, demonstrates a potential therapeutic role for the combination of an HMA and tagraxofusp in CMML. Further in vitro data from primary patient samples, including impact of single and dual agent therapy on immunophenoytpe and clonal architecture, as well as in vivo efficacy data, will be presented. [Display omitted] DisclosuresChen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Rampal:Constellation: Research Funding; Celgene: Honoraria; Jazz: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; Stemline: Research Funding.

Proteomic Landscape of Neutrophils in Sickle Cell Anemia: An Unexpected Autoimmune Profile

Although sickle cell disease (SCD) is a red cell disorder, many cell types, including endothelial cells and polymorphonuclear neutrophils (PMNs), contribute to its pathophysiology. In particular, activated PMNs have been implicated to play an important role in the initiation and propagation of vaso-occlusive events in SCD. Activated PMNs engage in a complex process of abnormal interactions with activated endothelial cells, platelets and circulating erythrocytes contributing to endothelial injury and decreased blood flow. In the present study, global proteomic analysis was performed using label-free mass spectrometry of PMNs from 4 SCD patients (SS) in steady state and from 4 control subjects (AA). We identified a total of 4,534 proteins both in AA and SS PMNs with 3,080 of these proteins identified in at least three samples for each condition. 50 proteins were significantly over-expressed in SS PMNs compared to AA PMNs (ratio > 1.4). STRING employed to monitor potential interaction between the overexpressed proteins showed that the main interactive clusters consist of STAT1 and STAT2, OAS 1, 2 and 3, and many Interferon Signaling Proteins i.e. IFIT1, IFIT2, IFIT 3, ISG15, ISG20, GBP2, IFI35, MX1 and MX2, TLR8 proteins (Fig. 1). This finding implies a strong activation of the type I interferon (IFN) signaling pathway in the SS PMNs (between 10 and 100-fold increase in SS vs AA). In addition, 33 proteins showed significantly lower expression in SS PMNs compared to AA PMNs. Among these were L-selectin (CD62L) and IL-17 receptor A (IL17RA) (p = 0.01). These findings are consistent with previously described phenotypes of aged neutrophils and acute inflammatory responses in SCD.Similar proteomic analysis performed on PMNs from SS patients treated with hydroxycarbamide (HC, n=4) showed that 14 proteins had significantly lower expression compared to untreated-SS patients (ratio <0.7). Interestingly, HC restored a normal expression pattern for most of the interferon signaling proteins.Type I IFNs represent the major effector cytokines of the host immune response against viruses and other intracellular pathogens. These cytokines are produced via activation of STAT1 and of pattern recognition receptors, including the Toll-like receptor signaling network. To determine if type I IFN-α could be detected at the protein level in the plasma of SS patients, we used the novel digital-ELISA technology (SIMOA, Quanterix) developed by Wilson et al (J Lab Autom, 2016). Interestingly, we found an increased level of INFα in plasma from SS patients compared to AA (n=32) (p<0.001) and it is noteworthy that while 50% of SS patients have similar level of INFα compare to AA individuals the other 50% exhibit 10 to 1,000-fold increased levels (Fig. 2).In summary, our novel proteomic analysis documents a high level expression of interferon signaling proteins, STAT1 and TLR8 in the proteome of neutrophils from SS patients and strongly suggests autoimmune or auto-inflammatory phenomena at basal state in SCD. Our results provide strong support for an important role for the innate immune system in the pathophysiology of SCD. Future studies will help determine the relationship between the plasmatic level of IFN-α and clinical complications and will establish if interferon signaling proteins and IFN-α could represent new therapeutic targets in SCD. [Display omitted] DisclosuresHermand-Tournamille:Imara: Research Funding. Le Va Kim:Imara: Research Funding. Koehl:Imara: Research Funding.

Antinuclear antibody and rheumatoid factor positivity in temporomandibular disorders

BackgroundTo investigate the differences in clinical characteristics and long-term treatment outcomes according to antinuclear antibody(ANA) and rheumatoid factor(RF) positivity and the correlation between pain-related and hematological indices in temporomandibular disorders(TMD) patients.MethodsClinical examinations were done following the Research Diagnostic Criteria for TMD in 257 patients. Comprehensive screening along with psychological and hematological evaluations (ANA, RF, complete blood cell count, C-reactive protein[CRP] and erythrocyte sedimentation rate[ESR]) were conducted. Clinical characteristics and treatment outcomes were statistically compared between ANA/RF positive and negative groups.ResultsThirty-nine patients showed ANA/RF positivity. Male patients had smaller comfortable mouth opening(CMO)(p = 0.033) and maximum mouth opening(MMO)(p = 0.016) ranges with more painful neck muscles on palpation when RF/ANA positive. Pain duration, intensity, disability days and psychological distress levels were also higher in RF/ANA positive male patients. Significant correlation was shown in ESR with pain duration(p < 0.05) and numeric rating scale(NRS) before treatment(p < 0.05), CRP with NRS before treatment(p < 0.01), and red blood cell (RBC) with pain intensity(p < 0.05), NRS before treatment(p < 0.01), CMO(p < 0.01), pain on palpation of cervical muscles(p < 0.01), CMO(p < 0.05), and MMO(p < 0.05) 6 months after treatment.ConclusionsThese results may point towards a nonspecific autoimmune disposition in a subgroup of TMD patients. RF and ANA could be considered as a screening test for the detection of autoimmune phenomena in TMD.

Hypothesis: Clues From Mammalian Hibernation for Treating Patients With Anorexia Nervosa.

This hypothesis is that anorexia nervosa (AN) is a biologically driven disorder, and mammalian hibernation may offer clues to its pathogenesis. Using this approach, this hypothesis offers suggestions for employing heart rate variability as an early diagnostic test for AN; employing the ketogenic diet for refeeding patients, attending to omega 3:6 ratio of polyunsaturated fatty acids (PUFAs) in the refeeding diet; and exploring clinical trials of the endocannabinoid-like agent, palmitoylethanolamde for patients with AN. This hypothesis also explores the role of lipids and autoimmune phenomena in AN, and suggest a lipodomics study to search for antibodies in the serum on patients with AN.

57-Year-Old Man With Atypical Chest Pain

57-Year-Old Man With Atypical Chest Pain

Congenital neutropenia and primary immunodeficiency diseases.

Neutropenia is a dangerous and potentially fatal condition that renders patients vulnerable to recurrent infections. Its severity is commensurate with the absolute count of neutrophil granulocytes in the circulation. In paediatric patients, neutropenia can have many different aetiologies. Primary causes make up but a small portion of the whole and are relatively unknown. In the past decades, a number of genes has been discovered that are responsible for congenital neutropenia. By perturbation of mitochondrial energy metabolism, vesicle trafficking or synthesis of functional proteins, these mutations cause a maturation arrest in myeloid precursor cells in the bone marrow. Apart from these isolated forms, congenital neutropenia is associated with a multiplicity of syndromic diseases that includes among others: oculocutaneous albinism, metabolic diseases and bone marrow failure syndromes. Congenital neutropenia is a primary immunodeficiency disease that is associated with recurrent bacterial infections, auto-inflammatory and auto-immune phenomena, haematological malignancy and neuro-psychiatric manifestations. The aim of this review is to give a comprehensive overview of the most recent literature concerning the clinical, aetiological and genetic features of congenital neutropenia and the syndromes in which it might be encountered.

Anti‑osteopontin autoantibodies in various types of cancer.

The aberrant processing of biomolecules by cancer cells may give rise to autoimmune phenomena. The metastasis gene osteopontin is alternatively spliced only in transformed cells, and the variants promote tumor progression. They may also serve as tumor‑associated antigens, and their neutralization by autoantibodies could favorably affect prognosis. A competitive solid‑phase ELISA format was applied to determine reactivity toward recombinant osteopontin in human serum or plasma samples. Approximately 35% of thyroid cancer patients and 15% of other cancer patients were found to harbor autoantibodies directed to osteopontin variants, averaging 21% of patients across all cancers studied. The reactivity of the autoantibodies was consistent with the differential appearance of splice variants in individual malignancies. In thyroid cancer, autoantibodies were found to be more frequently associated with a milder form of the disease. The junctions of osteopontin splice variants produced by cancers represent tumor‑associated neo‑epitopes. Whereas the uniqueness of their sequences renders the acquisition of tolerance during immune maturation improbable, their immunogenicity is predicted to be low. The rare occurrence of antibodies to either osteopontin‑b or osteopontin‑c suggests that the breaking of tolerance to full‑length osteopontin is more prevalent in tumor autoimmunity than a reaction to a poorly immunogenic neo‑epitope.

Expression of CD markers in JAK2V617F positive myeloproliferative neoplasms: Prognostic significance.

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by the presence of JAK2V617F mutation. Thrombohemorrhagic as well as autoimmune or inflammatory phenomena are common clinical outcomes of these disorders. Recent studies have shown that abnormality in frequency and function of blood cells manifested by an alteration in CD markers’ expression patterns play a key role in these complications. So, there may be a relationship between CD markers’ expressions and prognosis of JAK2V617F positive MPNs. Therefore, in this review, we have focused on these abnormalities from the perspective of changing expressions of CD markers and assessment of the relationship between these changes with prognosis of JAK2V617F positive MPNs. It can be stated that the abnormal expression of a large number of CD markers can be used as a prognostic biomarker for clinical outcomes including thrombohememorrhagic events, as well as autoimmune and leukemic transformation in JAK2V617F positive MPNs. Considering the possible role of CD markers’ expressions in JAK2V617F MPNs prognosis, further studies are needed to confirm the relationship between the expression of CD markers with prognosis to be able to find an appropriate therapeutic approach via targeting CD markers.

42. Consumption of Swietenia macrophylla seeds can lead to hepatitis and autoimmune phenomena

42. Consumption of Swietenia macrophylla seeds can lead to hepatitis and autoimmune phenomena

Alopecia areata: a review of disease pathogenesis.

Alopecia areata is a disorder that results in nonscarring hair loss. The psychological impact can be significant, leading to feelings of depression and social isolation. Objectives In this article, we seek to review the pathophysiological mechanisms proposed in recent years in a narrative fashion. We searched MEDLINE and Scopus for articles related to alopecia areata, with a particular emphasis on its pathogenesis. The main theory of alopecia areata pathogenesis is that it is an autoimmune phenomenon resulting from a disruption in hair follicle immune privilege. What causes this breakdown is an issue of debate. Some believe that a stressed hair follicle environment triggers antigen presentation, while others blame a dysregulation in the central immune system entangling the follicles. Evidence for the latter theory is provided by animal studies, as well investigations around the AIRE gene. Different immune-cell lines including plasmacytoid dendritic cells, natural killer cells and T cells, along with key molecules such as interferon-γ, interleukin-15, MICA and NKG2D, have been identified as contributing to the autoimmune process. Alopecia areata remains incurable, although it has been studied for years. Available treatment options at best are beneficial for milder cases, and the rate of relapse is high. Understanding the exact mechanisms of hair loss in alopecia areata is therefore of utmost importance to help identify potential therapeutic targets.