Anti-histone Antibodies Research Articles

EP(ILEPT)IC COMPLICATIONS

EP(ILEPT)IC COMPLICATIONS

DYSPNEIC AFTER EVERY COVID-19 SHOT: SUSPECTED BNT162B2 MRNA VACCINE-RELATED, DRUG-INDUCED PULMONARY EOSINOPHILIA

DYSPNEIC AFTER EVERY COVID-19 SHOT: SUSPECTED BNT162B2 MRNA VACCINE-RELATED, DRUG-INDUCED PULMONARY EOSINOPHILIA

A pro-oxidant combination of resveratrol and copper down-regulates hallmarks of cancer and immune checkpoints in patients with advanced oral cancer: Results of an exploratory study (RESCU 004).

BackgroundOur earlier studies have shown that cell-free chromatin particles (cfChPs) that are released from dying cancer cells are readily internalised by bystander cells leading to activation of two hallmarks of cancer viz. genome instability and inflammation. These hallmarks could be down-regulated by deactivating cfChPs via medium of oxygen radicals generated upon admixing small quantities of the nutraceuticals resveratrol (R) and copper (Cu). In this exploratory study, we investigated whether oral administration of R and Cu (R-Cu) would down-regulate the hallmarks of cancer and immune checkpoints in advanced squamous cell carcinoma of oral cavity (OSCC).Patients and methodsThe study comprised of 25 patients divided into 5 equal groups. Five patients acted as controls; the remaining 20 were given R-Cu in four escalating doses. The lowest dose of R-Cu was 5.6mg and 560ng respectively, and the highest dose was 500mg and 5mg respectively. An initial biopsy was taken from patients at first presentation, and a second biopsy was taken 2 weeks later on the operating table. R-Cu was administered orally twice daily in the intervening period. Confocal microscopy was performed on tumour sections after fluorescent immuno-staining with anti-DNA and anti-histone antibodies to detect presence of cfChPs in the tumour micro-environment (TME). Immunofluorescence analysis was performed for 23 biomarkers representing the 10 Hallmarks of cancer, including 5 immune checkpoints, defined by Hanahan and Weinberg.ResultsConfocal microscopy detected copious presence of cfChPs in TME of OSCC, which were eradicated/deactivated following two-week treatment with R-Cu. Eradication of cfChPs from TME was associated with marked down-regulation of 21/23 biomarkers, including the five immune checkpoints. The lower two doses of R-Cu were more effective than the higher doses. No adverse effects attributable to R-Cu were observed.ConclusionThese results suggest that cfChPs released into TME from dying cancer cells are global instigators for cancer hallmarks and immune checkpoints in surviving cancer cells. The ability of R-Cu to deactivate cfChPs raises the prospect of a novel and non-toxic form of cancer treatment which sans killing of cancer cells, and instead induces healing by down-regulating cancer hallmarks and immune check-points.Clinical Trial Registration http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19801&EncHid=&userName=CTRI/2018/03/012459.

Anti-histone H3.3K36M Antibody is a Highly Sensitive and Specific Immunohistochemistry Marker for the Diagnosis of Chondroblastoma. A Validation Based on Study 136 Cases Comprising Chondroblastoma and its Mimics from Single a Centre in India.

Introduction. Chondroblastoma has a wide range of differential diagnosis encompassing various benign and malignant entities. The closest differential diagnosis is giant cell tumor of the bone due to overlapping radiological and histomorphological features. Extensive aneurysmal bone cyst like changes and lack of adequately sampled chondroid matrix often masquerades the primary bone lesion and amplifies the diagnostic difficulty in small biopsies with limited tissue. Immunohistochemistry is helpful in such instances to resolve the diagnostic dilemma. Objectives. To analyze the immunohistochemical expression of anti-histone H3F3K36M antibody inchondroblastoma and validate its utility in differentiating chondroblastoma from its histological mimics. Material and methods. Immunohistochemistry was performed using anti-histone antibody H3.3K36M in 44 histologically diagnosed chondroblastoma and 92 other histological mimickers. All chondroblastoma and giant cell tumor of the bone included in the study were also tested for anti-histone H3.3 G34W antibody. Of the 33 giant cell tumors of bone with classic morphology and imaging findings, 24 H3.3 G34W positive and 9 negative tumors were included intentionally to rule out the possibility of chondroblastoma. The sensitivity, specificity, positive and negative predictive value of marker with regard to chondroblastoma was calculated. Results. Immunohistochemistry revealed unequivocal nuclear positivity for H3.3K36M in the mononuclear cells in all the 44 chondroblastoma tested, denoting a sensitivity of 100% cases. Allthesetumors tested simultaneously for anti-histone H3.3G34W were negative. None of the histological mimickers were positive H3.3K36M indicating a specificity of 100%. The positive and negative predictive value was 100%. Conclusion. H3.3K36M mutant antibody is highly sensitive and specific IHC marker and can be used as a valuable adjunct to distinguish chondroblastoma from its histological mimics especially on small biopsies.

Interpreting Rheumatology Laboratory Tests

Interpreting Rheumatology Laboratory Tests

Drug-Induced Lupus: A Forgotten Cause of Prolonged Pyrexia of Unknown Origin

The causes of a pyrexia of unknown origin (PUO) are broadly spread across infectious, malignant, or inflammatory conditions. The authors report a case of a 43-year-old female who initially presented with hypoxia and fevers secondary to a presumed acute viral or bacterial infectious pulmonary insult. However, fevers persisted despite pulmonary imaging remaining normal. The case subsequently evolved into a PUO with multiple lines of investigation proving inconclusive. No definitive diagnosis was made at the time of discharge; however, cessation of hydralazine was noted to coincide with the last of the patient’s fevers. Following the discharge, her anti-histone antibodies returned a positive result, and the diagnosis of drug-induced lupus was made with hydralazine as the presumed trigger.

Pearls for the diagnosis and possible pathophysiological mechanisms of valproic acid-induced lupus erythematosus: A literature review.

Background: Drug-induced lupus erythematosus (DILE) accounts for 10-15% of systemic lupus erythematosus (SLE) cases, with more than 100 pharmaceutical agents implicated in its development. Depending on the offending drug, clinical and serological manifestations present great variability and, thus, DILE may be overlooked in clinical practice. Valproic acid (VPA) - induced lupus erythematosus has not been analytically reported in the literature, rendering the recognition of such cases even more difficult.Objective: The aim of this study was to analyze VPA - induced lupus features and to discuss possible pathophysiological mechanisms.Materials and Methods: This literature review was conducted in PubMed and Embase databases in June 2021, in search of DILE cases induced by VPA. We found 164 manuscripts, out of which 140 articles regarding other adverse effects or drugs were discarded. Finally, 15 cases fulfilled the eligibility criteria to be included in this review.Results: Although SLE is more common in females, VPA-induced lupus presented a male predilection. Patients developed DILE within the first three months of treatment with VPA at a percentage of 50%, whereas four patients from one to five years after VPA initiation. DILE frequently presented with mild symptoms. In most patients, serositis manifested with polyarthritis, pleural effusion or pericarditis. Notably, one patient presented with Rowell's syndrome, a rare subtype of lupus erythematosus with erythema multiforme and speckled pattern of antinuclear antibodies (ANAs). Central nervous system, renal and skin involvement was scarcely observed. Cytopenia was noted in 7 patients. Immunological findings included positive ANAs in the vast majority of the patients (86.7%), positive anti-histone antibodies in five, positive anti-dsDNA antibodies in three and hypocomplementemia in two patients. Despite the prompt resolution of clinical symptoms after VPA discontinuation, serological abnormalities persisted up to 18 months. Apart from the discontinuation of VPA administration for the resolution of DILE, treatment included corticosteroids in 8 cases.Conclusion: Valproic acid has been implicated in several cases of DILE. Clinicians should be aware of this entity and recognize it promptly to ensure a favorable outcome. Possible pathophysiologic associations may be extrapolated, but a clearer understanding of this syndrome is to be gained by further studies.

Study about Multisystem Autoimmune Disorder: Systemic Lupus Erythematosus, A Third World Prodigy

Childhood-onset Systemic Lupus Erythematosus (SLE) has an incidence of 0.3-0.9/100,000 children. It is very rare to find a case of childhood-onset SLE before 5 years of age. We describe a case of a 4-year-old female child, from a low-socioeconomic background who was diagnosed with SLE based on a typical rash, oral ulcer, positive laboratory parameters such as ANA, anti-ds DNA, anti-nucleosome, anti-histone antibodies, and positive lupus anticoagulants. There was an involvement of each system with considerable signs and symptoms including lupus nephritis, a cardiological complication such as Libman-Sack endocarditis, and neurological manifestations showing diffuse cerebral atrophy. The child was also positive for parameters linking to the presence of Macrophage Activation Syndrome MAS). The hypercoagulable state of SLE has been linked to more central nervous system involvement, cardiovascular dysfunction, renal complication, and hyponatremia as indicated in our case making it more riveting.

Anti-Histone H3.3 G34W antibody is a sensitive and highly specific immunohistochemistry marker for the diagnosis of Giant cell tumor of bone. A validation based on analysis of 198 cases from a single centre in India.

The diagnosis of giant cell tumor of bone (GCTB) is difficult in small biopsies with unusual age of presentation, location, and extensive secondary changes. Most of the GCTBs harbor H3F3A G34W mutations with a subset of cases showing alternate G34V, G34R, and G34L mutations. To analyze the expression of anti-histone H3.3G34W antibody in different cellular components of GCTB across different locations and presentations (including the unusual ones) and validate the utility of this antibody in the diagnosis of GCTB and differentiate it from the other osteoclast-like giant-cell-rich lesions. Immunohistochemistry was performed using anti-histone H3.3G34W antibody in the diagnosed cases of GCTB (136 cases of GCTB from 133 patients, including two malignant GCTBs) and other giant cell-containing lesions (62 cases). The presence of unequivocal crisp nuclear staining was considered positive. Immunohistochemistry revealed unequivocal nuclear positivity in the mononuclear cells in 87.3% of the cases of GCTB. Of these, most showed diffuse expression with moderate to strong intensity staining. The positive staining was restricted to the nuclei of mononuclear cells with the nuclei of osteoclastic giant cells being distinctly negative. In addition to conventional GCTBs, two cases each of multicentric and malignant GCTB showed positive staining. The other giant-cell containing lesions were distinctly negative. The present study showed a sensitivity of 87.3% with specificity and positive predictive value of 100%. The anti-histone G34W antibody is a highly sensitive and specific marker for the diagnosis of GCTB and differentiating it from its mimics. The positive staining is restricted to the mononuclear cell component of GCTB with sparing the osteoclastic giant cells further reiterating the fact that the mononuclear stromal cells are the true neoplastic component of GCTB.

Analyses of the clinical and immunological characteristics of patients with lupus erythematosus.

Background:Lupus erythematosus (LE) is a broad-spectrum, heterogeneous disease. At one end of the spectrum is the cutaneous LE (CLE) without systemic involvement, and at the other end is the systemic LE (SLE) with multisystem involvement. Analyses of clinical and immunological indicators and pathological examinations are helpful for early diagnosis, differential diagnosis, and prognosis of LE.Aim and Objectives:We described the clinical and laboratory characteristics of patients with LE and assessed the diagnostic value of immunohistochemical detection of C3d, C4d, IgG, IgG4, and CD123 in skin lesions of LE.Materials and Methods:Clinical and laboratory data of 62 patients with LE were collected. The expression levels of C3d, C4d, IgG, IgG4, and CD123 in skin lesions of LE were detected by immunohistochemistry (IHC).Results:Clinical manifestations such as hematological involvement, C3, C4, ESR, hematuresis, proteinuria, anti-Sm, anti-ribosomal P-protein, anti-U1-RNP, anti-histone, and anti-nucleosome antibodies are helpful for classificatory diagnosis of LE. The positive rate of C3d and/or C4d along the basement membrane zone in LE skin lesions by IHC was 74.6%, which was higher than that by direct immunofluorescence (47.5%) (P = 0.002). The expression of CD123 protein and the number of CD123+ plasmacytoid dendritic cells (PDCs) in skin lesions of patients with LE were higher than those of dermatomyositis (DM), while the distributed form of CD123 + PDCs in the dermis was different between LE and DM.Conclusions:The diagnosis of CLE and SLE requires a combination of clinical manifestations, laboratory indicators, and pathological examination. Immunohistochemical detection of C3d, C4d, and CD123 in skin lesions is important for the classificatory diagnosis of LE.

Acute Kidney Injury and Proteinuria in a Man With Hemoptysis

Acute Kidney Injury and Proteinuria in a Man With Hemoptysis

S2153 A Case of Proton Pump Inhibitor Causing Systemic Drug-Induced Lupus

Introduction: Drug induced lupus erythematosus (DILE) is a well documented autoimmune phenomenon that can be triggered by exposure to certain medications. Presented here is a case of systemic drug induced lupus erythematosus from a proton pump inhibitor (PPI), which represents a fairly uncommon reaction to this medication. Case Description/Methods: A 63 year old female with history of gastroesophageal reflux disease (GERD) presented to clinic complaining of typical heartburn pain and globus sensation for which she was prescribed pantoprazole. After 2 weeks of daily use, she developed pain and swelling of bilateral metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints, photosensitive malar rash, patchy alopecia, ‘gnawing’ diffuse abdominal pain (different than GERD symptoms), and oral ulcers. Her pantoprazole was stopped, and 2 weeks later her symptoms resolved. Review of the her medical record revealed that she had prior exposure to 2 other PPI's in the past that both were associated with development of similar symptoms. Use of omeprazole caused pain and swelling of her right MCP joints, and several years later use of esomeprazole caused severe pain and swelling of the left elbow. In both cases, discontinuation of her PPI caused resolution of symptoms. Her labs were notable for positive anti histone antibody and negative ANA, dsDNA, RF, anti CCP. Discussion: DILE has three basic variants; systemic, subacute cutaneous, and chronic cutaneous. The type of drug induced lupus and severity of symptoms is strongly associated with the specific drug of exposure. PPI's are most associated with subacute cutaneous DILE, although this remains an overall rare adverse reaction. Subacute cutaneous DILE presents with formation of annular or papulosquamous skin lesions and mild (if any) systemic symptoms. Our case is more consistent with systemic DILE. Review of literature reveals few case reports of systemic DILE from PPI use. Systemic DILE presents with multi-system involvement with constitutional symptoms, myalgias, arthralgias, and serositis. Symptoms resolve with withdrawal of the agent. The case above clearly demonstrates this illness script through multiple exposures to PPI. Classic SLE is ruled out in this case due to this temporal relationship with drug exposure, as well as her antibody profile positive for anti-histone and negative for other SLE-associated antibodies. This case highlights the importance of considering atypical drug reactions, even when prescribing relatively common medications.

Infliximab (an antitumor necrosis factor) induced lupus in a patient with inflammatory bowel disease

Infliximab is a monoclonal antibody that works by inhibiting the proinflammatory cytokine and tumor necrosis factor-alpha. Systemic lupus erythematosus is an autoimmune disease that affects multiple organs, and its pathogenesis involves abnormal immune complexes, environment factors, and genetics. Several reports have documented a controversy regarding infliximab-induced lupus disease. This paper reports on infliximab-induced lupus in an 18-year-old Saudi female having short stature, hypogonadism, and Crohn's disease with ileocolonic fistula. The patient developed reactive arthritis, and serology showed positive anti-double strand DNA and antihistone antibodies after infliximab administration, suggesting drug-induced lupus. More cohort studies are recommended to monitor the presentation and reversibility of infliximab-induced lupus disease.

27989 An unusual presentation of acute generalized exanthematous pustulosis (AGEP) in pregnancy

A 39-year-old female at 23 weeks’ gestation presented with a four-day history of diffuse pustules that developed acutely on her abdomen and rapidly spread. She denied any associated symptoms, personal or family history of skin disorders, and review of systems was negative. Her medications included omeprazole for gastroesophageal reflux disease and a prenatal vitamin. Physical examination revealed enumerable pustules over the abdomen and flanks with background erythema; erythematous macules and papules coalescing into edematous plaques with enumerable overlying pustules on the anterior lower extremities; scattered erythematous macules on the upper extremities; and rare pustules on the chest and neck. The differential diagnosis included acute generalized exanthematous pustulosis (AGEP), pustular psoriasis of pregnancy (PPP), and pemphigoid gestationis. Two punch biopsies were performed for hematoxylin and eosin stain (H&E) and direct immunofluorescence (DIF) respectively. Biopsy for H&E demonstrated modest spongiosis with spotty microfoci of neutrophilic exocytosis, tiny parakeratotic mounds with entrapped neutrophils, and scattered neutrophils in the papillary dermis with rare eosinophils. DIF demonstrated patchy segmental granular IgM deposition along the dermoepidermal junction and granular C3 deposition along the dermoepidermal junction. Laboratory workup including complete blood count, comprehensive metabolic panel, ionized calcium, parathyroid hormone, anti-neutrophilic antibody, anti-histone antibodies, anti-double-stranded DNA antibodies, and anti-Smith antibodies were unremarkable. Triamcinolone 0.1% ointment twice daily and discontinuation of omeprazole resulted in the complete resolution of the pustules. Given the rapid improvement with topical steroids and discontinuation of omeprazole in conjunction with the lack of systemic symptoms, the patient was diagnosed with AGEP secondary to omeprazole.

S2k guideline: Diagnosis and management of cutaneous lupus erythematosus - Part1: Classification, diagnosis, prevention, activity scores.

S2k guideline: Diagnosis and management of cutaneous lupus erythematosus - Part1: Classification, diagnosis, prevention, activity scores.

Differential Regulation of Damage-Associated Molecular Pattern Release in a Mouse Model of Skeletal Muscle Ischemia/Reperfusion Injury

BackgroundSkeletal muscle ischemia/reperfusion (I/R) injury is an important clinical issue that can cause remote organ injury. Although its pathogenesis has not been fully elucidated, recent studies have suggested that damage-associated molecular patterns (DAMPs) are mediators of remote organ injury in sterile inflammation. The purpose of this study was to investigate the possible involvement of DAMPs, including the nuclear proteins high-mobility group box 1 (HMGB1) and histone H3, in the pathogenesis of skeletal muscle I/R injury in mice.MethodsHindlimb ischemia was induced in mice through bilateral ligation of inguinal regions using rubber grommets. Reperfusion was induced by cutting the rubber grommets after 2–12 h of ischemic period. Survival rates, localization of HMGB1 and histone H3 in the gastrocnemius muscle, and circulating HMGB1 and histone H3 levels were analyzed. The effect of anti-HMGB1 and anti-histone H3 antibodies on survival was analyzed in mice with I/R injury.ResultsAll mice with hindlimb ischemia survived for at least 36 h, while all mice died within 24 h if the hindlimbs were reperfused after ischemia for 4–12 h. Immunohistochemical analysis revealed that HMGB1 translocated from the nucleus to the cytoplasm in the ischemic gastrocnemius muscle, while histone H3 was confined to the nucleus. Accordingly, serum HMGB1 levels were significantly elevated in mice with hindlimb I/R compared with normal mice or mice with hindlimb ischemia (P < 0.05). Serum histone H3 levels were not elevated after I/R. Treatment with anti-HMGB1 antibodies significantly improved survival of mice with hindlimb I/R injury compared with control antibodies (P < 0.05).ConclusionsHMGB1, but not histone H3, translocated to the cytoplasm during skeletal muscle ischemia, and was released into the systemic circulation after reperfusion in mice with I/R injury. Treatment with anti-HMGB1 antibodies partially improved survival.

Abstract 2514: Cell-free chromatin particles released into the microenvironment from dying tumor cells activate cancer hallmarks in surviving cells: a study in advanced squamous cell carcinoma of oral cavity with therapeutic implications

Abstract Background: We have reported that combination of the nutraceuticals Resveratrol (R) and Copper(Cu) results in generation of free radicals which can degrade cell-free chromatin (cfCh) particles and have potential therapeutic effects (Mittra et al., Ann. Oncol. 2017 &amp; Mittra et al., PLos One 2020). We have also reported that cfCh particles that are released from dying tumor cells can integrate into genomes of healthy bystander cells to activate two critical hallmarks of cancer namely, genome instability and inflammation, which could lead to their oncogenic transformation (Mittra et al., Cell Death Discovery 2017). Here we show that cfCh particles released into tumor microenvironment (TME) from dying tumor cells of advanced squamous carcinoma of oral cavity activate all ten hallmarks of cancer defined by Hanahan and Weinberg, and that oral administration of R-Cu for two weeks prevents this potentially life-threatening manifestation. Patients and Methods: The study was approved by Institutional Ethics Committee, and a written consent was obtained from participants. In this exploratory study, R-Cu was administered in four escalating doses orally for two weeks, to 25 patients divided into 5 groups with 5 patients each, as follows: 1) Control: R 0, Cu 0; 2) Level I: R 5.6 mg, Cu 560 ng; 3) Level II: R 50 mg, Cu 5µg; 4) Level III: R 500 mg, Cu 50 µg; 5) Level IV: R 500 mg, Cu 5mg. A punch biopsy was obtained on the day 0 and day 14 post R-Cu treatment. FFPE histological sections were examined by 1) Fluorescence immuno-staining (FI) using anti-DNA and anti-histone H4 antibodies and confocal microscopy to detect presence of cfCh in TME; 2) Immuno-fluorescence (IF) analysis of intracellular antioxidant enzymes; and 3) IF analysis of 10 hallmarks of cancer represented by 23 biomarkers. Results: 1) FI and Confocal microscopy detected extensive presence of dually fluorescently labelled cfCh particles in TME, which were dramatically reduced following R-Cu treatment. 2) IF analysis detected significantly elevated levels of three intra-cellular anti-oxidant enzymes in post R-Cu samples, suggesting that cells had mounted a defense mechanism to counteract free radicals that had entered into them. No difference between day 0 and day 14 samples was seen in the untreated control group. 3) IF analysis of 23 cancer hallmark biomarkers showed significant down-regulation in the post R-Cu samples, which were most marked in dose levels I and II. No difference between day 0 and day 14 samples was seen in the control group. Conclusion: We show in a human tumor model that cfCh particles released into TME from dying tumor cells activate cancer hallmarks in surviving cells, and that the cfCh inactivating agent R-Cu can significantly down-regulate cancer hallmark levels suggesting its therapeutic potential. Citation Format: Indraneel Mittra, Hitesh Singhavi, Aishwarya Pilankar, Venkat Raghuram Gorantla, Sophiya Siddiqui, Naveen Kumar Khare, Vishalkumar Jadhav, Kavita Pal, Pankaj Chaturvedi. Cell-free chromatin particles released into the microenvironment from dying tumor cells activate cancer hallmarks in surviving cells: a study in advanced squamous cell carcinoma of oral cavity with therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2514.

Anti-neutrophil cytoplasmic antibody associated glomerulonephritis complicating treatment with hydralazine

Hydralazine, a widely used therapy for hypertension and heart failure, can elicit autoimmune disease, including anti-neutrophil cytoplasmic antibody associated glomerulonephritis (ANCA-GN). We identified 80 cases of ANCA-GN complicating treatment with hydralazine, accounting for 4.3% (80/1858 biopsies) of ANCA-GN diagnosed between 2006 and 2019. Over three-fourths of patients were on hydralazine for at least one year, with mean daily dose of approximately 250 mg/day. ANCA testing revealed p-ANCA/myeloperoxidase-ANCA seropositivity in 98%, including 39% with dual p-ANCA/myeloperoxidase-ANCA and cANCA/anti-protinase 3-ANCA positivity, often accompanied by anti-nuclear antibody (89%), anti-histone antibody (98%), and hypocomplementemia (58%). Kidney biopsy revealed necrotizing and crescentic glomerulonephritis, similar to primary ANCA-GN, but significantly less frequently pauci-immune (77 vs. 100%) and more commonly associated with mesangial hypercellularity (30 vs. 5%), electron dense deposits (62 vs. 20%), and endothelial tubuloreticular inclusions (11 vs. 0%); all significant differences. On follow-up, 42 of 51 patients received induction immunosuppression: 19 reached the combined end-points of kidney failure or death and 32 had mean creatinine of 1.49 mg/dL at last follow-up. Thus, hydralazine-associated ANCA-GN often exhibits overlapping clinical and pathologic features of mild immune complex glomerulonephritis resembling lupus nephritis. With discontinuation of hydralazine and immunosuppression, outcomes are similar to primary ANCA-GN.

Histone-DNA Complexes and Coagulation after Intracerebral and Subarachnoid Hemorrhage.

Intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) have limited treatment options and a high mortality. We have previously shown that both conditions are associated with early hypercoagulation. 1 2 Histones have been demonstrated to promote thrombin generation. 3 In sepsis and trauma patients, studies have revealed an association between histone-DNA complexes and free histone levels and mortality or morbidity. 4 5 6 Theoretically, the effects on coagulation of histones can be investigated in vitro by attempting to block histones with specific antibodies. The aim of this study was to quantify histone-DNA complex levels in patients with ICH or SAH at the time of admission to hospital compared with 24 hours after symptom onset and to investigate the possible in vitro effect of anti-histone antibodies on thrombin generation.

Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation.

ABSTRACTMyeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined.Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as Baff, Il5, Il9 and Cd40L, affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance.Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity.