Autoimmune Deficiency Research Articles

On the modeling and analysis of the biological regulatory network of NF-$${\kappa }$$B activation in HIV-1 infection

AbstractPurposeThe complex interactions between genetic machinery of HIV-1 and host immune cells mediate dynamic adaptive responses leading to Autoimmune Deficiency Syndrome. These interactions are captured as Biological Regulatory Network (BRN) which acts to maintain the viability of host cell machinery through feedback control mechanism which is a characteristic of complex adaptive systems. In this study, the BRN of immune response against HIV-1 infection is modeled to investigate the role of NF-κB and TNF-α in disease transmission using qualitative (discrete) and hybrid modeling formalisms.MethodsQualitative and Hybrid modeling approaches are used to model the BRN for the dynamic analysis. The qualitative model is based on the logical parameters while the hybrid model is based on the time delay parameters.ResultsThe qualitative model gives useful insights about the physiological condition observed as the homeostasis of all the entities of the BRN as well as pathophysiological behaviors representing high expression levels of NF-κB, TNF-α and HIV. Since the qualitative model is time abstracted, so a hybrid model is developed to analyze the behavior of the BRN by associating activation and inhibition time delays with each entity. HyTech tool synthesizes time delay constraints for the existence of homeostasis.ConclusionHybrid model reveals various viability constraints that characterize the conditional existence of cyclic states (homeostasis). The resultant relations suggest larger cycle period of HIV-1 than the cycle periods of the other two entities (NF-κB and TNF-α) to maintain a homeostatic expressions of these entities.

Abstract B003: Developing an analytical method for second messenger cyclic GMP-AMP

Abstract The presence of double-stranded DNA (dsDNA) in the cytosol is a danger signal associated with microbial infections and tumor microenvironment. The cytosolic DNA surveillance pathway (CDSP) is critical for sensing such signal to elicit type I interferon response, which facilitates infection clearance and tumor rejection. Uncontrolled engagement of CDSP is also linked to autoimmune disease. The key components of CDSP are the DNA sensor—cyclic GMP-AMP synthase (cGAS), the second messenger—cyclic GMP-AMP (cGAMP), and the endoplasmic reticulum localized adaptor—stimulator of interferon inducible genes (STING). While numerous efforts, including ours, are focusing on developing STING agonists formulated cancer vaccine, an analytical method that is sensitive and reliable for cGAMP and other cyclic dinucleotides is also in high demand to enable quantitative investigations. In this work, we developed and optimized a rapid quantification workflow that integrates solid phase extraction, hydrophilic liquid chromatography and multiple reaction monitoring mass spectrometry. This workflow enables detection of cGAMP in cells at sub-femtomole levels and is amenable for scaling up for high throughput analysis. A biochemically synthesized nonradioactive isotope labeled cGAMP standard enables absolute quantification. As a proof of principle, this method is first applied to probe cGAMP in macrophages infected with Mycobacterium tuberculosis, and to help establish cGAS as the innate immune sensor for the pandemic pathogen. Second, constitutive levels of cGAMP in organs of autoimmune mouse models, of Trex1 or Dnase2 deficiencies, are quantified. The result indicates a direct engagement of the cGAS-cGAMP-STING pathway in the autoimmune pathology. Finally, we show that cGAMP is produced when the apoptosis program is initiated in conjunction with pro-apoptotic caspase inhibition. This shows that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. Altogether, these studies demonstrated the usefulness of this analytical method for quantifying cGAMP in a high dynamic range under different biological contexts. We are currently applying this method to measure the activation of the cGAS pathway in tumor immunity and immunotherapy. Citation Format: Tuo Li, Zhijian J. Chen. Developing an analytical method for second messenger cyclic GMP-AMP. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B003.

Longitudinal behavior of autoimmune GH deficiency: from childhood to transition age

Some cases of apparently idiopathic GH deficiency (GHD) may be caused by pituitary autoimmunity. To study the variations in pituitary function and antipituitary antibodies (APA) from childhood to transition age in patients with apparently idiopathic GHD. We conducted a longitudinal study. Pituitary function and APA detection by immunofluorescence were investigated in 24 childhood patients with isolated GHD before starting recombinant GH therapy and after the stopping of this therapy in transition age. Sera of patients positive for APA were processed by double immunofluorescence to identify their pituitary target. At diagnosis, 16 out of 24 patients were APA positive targeting only somatotrophs (group 1), while the remaining eight were APA negative (group 2). When retested off therapy, 12 out of 16 patients in group 1 persisted being APA positive, while the remaining four became negative with recovery of pituitary function. All patients in group 2 persisted being APA negative but still showing GHD. Of the 12 patients persistently APA positive, eight with confirmed GHD showed APA still targeting somatotrophs, whereas four showed APA targeting only gonadotrophs associated with isolated hypogonadotropic hypogonadism (HH). Patients with APA at middle but not at high titer in childhood may show a remission of autoimmune GHD in childhood after GH replacement therapy. As APA may shift their target in transition period, an early characterization of APA by double immunofluorescence is advisable in APA positive GHD patients showing delayed puberty, to allow an early diagnosis and an appropriate therapy, thus preventing the progression toward HH.

Tuberculosis concomitant with diabetes

The resurgence of tuberculosis and the appearance of multidrug-resistant strains of Mycobacterium tuberculosis are due to several different factors. Principal among these is the worldwide prevalence of autoimmune deficiency syndrome (AIDS), coupled with misdirected therapeutic practices and patient non-compliance, the latter being derived from the undesirable side effects of anti-tuberculosis drugs. Aside from AIDS, other diseases or immunosuppressive disorders have been associated with this new phase of tuberculosis infection. Metabolic disorders such as diabetes, which is closely associated with obesity, are among the most important immunosuppressive diseases. Diabetes is a major public health problem in Mexico, a country that leads the world in the incidence of childhood obesity.The aim of this study is to analyse the different factors involved in this phenomenon and to give a clear, comprehensive picture of the problem of tuberculosis resurgence and its correlation with diabetes and metabolic syndrome.

Abstract 2216: A novel G-quadruplex formed in the proximal P1 promoter of bcl-2 gene is a gene suppressor

Abstract Deregulation of bcl-2, an anti-apoptotic protein, is associated with several human diseases such as tumorigenesis, neurodegeneration, and autoimmune deficiencies. DNA G-quadruplex secondary structures that form in the G-rich proximal promoter regions have been found to play an important role in gene transcriptional regulation. We discovered a novel GC-rich sequence in the immediate proximal P1 promoter of the bcl-2 gene (bcl2P1Pu29), which forms a thermodynamically stable, intramolecular G-quadruplex (bcl2P1G4) that represses bcl-2 gene transcription. Dimethyl sulfate footprinting studies indicated that this bcl2 P1 promoter G-rich region forms G-quadruplexes under physiologically relevant ionic conditions. This was shown by clear DMS protection of guanine N7, which is characteristic of G-quadruplex formation. NMR spectroscopic study of bcl2P1Pu29 showed the formation of a well-defined major G-quadruplex structure under physiologically relevant ionic conditions, as evident by sharp peaks in the imino proton region. Interestingly, NMR data also indicated the presence of Watson-Crick base-pairing, suggesting a potential unique loop conformation. Circular dichroism (CD) studies suggested that bcl2P1G4 adopts parallel-stranded folding. Both NMR and CD data indicated a monomeric structure of bcl2P1G4 with high thermo-stability. Using a luciferase assay, we have shown that TMPyP4, a planar cationic G-quadruplex-interactive compound, significantly inhibits the promoter activity through this G-rich bcl-2 P1 promoter region, while TMPyP2, a positional isomer of TMPyP4 which is a poor G-quadruplex-interactive compound, did not show a significant effect. Our results suggest that this novel intramolecular G-quadruplex formed in the bcl-2 proximal promoter region appears to be a suppressor of gene transcription, which could be a potential molecular target for small molecules to modulate bcl-2 gene transcription. Citation Format: Buket Onel, Megan Carver, Danzhou Yang. A novel G-quadruplex formed in the proximal P1 promoter of bcl-2 gene is a gene suppressor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2216. doi:10.1158/1538-7445.AM2015-2216

Anti‐factor XIII A subunit (FXIII‐A) autoantibodies block FXIII‐A2B2 assembly and steal FXIII‐A from native FXIII‐A2B2

Autoimmune hemophilia-like disease (hemorrha-philia or hemorrhagic disorder) caused by anti-factorXIII antibodies (termed AH13) or 'autoimmune FXIII deficiency' is a life-threatening bleeding disorder. AH13 was thought to be rare worldwide. Because the number of diagnosed AH13 cases has recently been increasing, at least in Japan, we conducted a nationwide survey supported by the Japanese Ministry of Health, Labor, and Welfare, and explored the pathologic mechanism(s) of AH13. We diagnosed AH13 cases during the last 11years according to the presence of anti-FXIII autoantibodies confirmed by a dot blot assay and ELISA, and characterized 33 of these both immunologically and biochemically. The AH13 cases were immunologically classified into three types, Aa, Ab, and B. TypeAa autoantibodies, observed in 27 cases, were directed against the native FXIII A subunit (FXIII-A), and blocked FXIII activation. The autoantibodies not only prevented assembly of new FXIII-A2 B2 heterotetramers, but also removed FXIII-A from native FXIII-A2 B2 heterotetramers by forming an FXIII-A-IgG complex. TypeAb autoantibodies, detected in three cases, preferentially bound to activated FXIII-A and inhibited its activity. TypeAa and Ab autoantibodies were 'neutralizing' FXIII antibodies (or FXIII inhibitors), and thus could be screened with functional assays. TypeB antibodies, detected in two cases, were non-neutralizing anti-FXIII B subunit (FXIII-B) autoantibodies that possibly accelerated the clearance of FXIII, and thus could be diagnosed exclusively with immunologic methods. There are three major types of anti-FXIII autoantibody, with distinct targets and mechanisms that cause AH13.

Acquired ataxias: the clinical spectrum, diagnosis and management.

Acquired ataxias represent a large group of disorders defined by the common clinical feature of ataxia and the absence of a clear genetic basis for it. Based on the aetiology, the group can be subdivided into autoimmune, toxic, infectious and vitamin deficiency causes. Cerebellar ataxia may occur as an isolated syndrome in this spectrum of disorders but is often accompanied by additional neurological manifestations. Clinical work-up is challenging and mainly includes biochemical analyses, whereas imaging is of minor significance. Diagnosis is essential as many of these disorders represent potential treatable conditions and early therapy may prevent progressive cerebellar ataxia. The clinical findings, the implications for diagnosis and management of this heterogeneous group of disorders are discussed in this review.

Autoimmune polyendocrine syndrome 3 onset with severe ketoacidosis in a 74-year-old woman.

Type 1 diabetes mellitus (T1D), autoimmune thyroid disease, and autoimmune gastritis often occur together forming the so-called autoimmune polyendocrine syndrome type 3 (APS3). We here report a clinical case of a 74-year-old woman who presented for the first time with severe hyperglycemia and ketoacidosis diagnosed as T1D. Further clinical investigations revealed concomitant severe hypothyroidism with autoimmune thyroid disease and severe cobalamin deficiency due to chronic atrophic gastritis. The diagnosis of type 1 diabetes mellitus was confirmed by the detection of autoantibodies against glutamic acid decarboxylase 65, islet cell antibodies, and anti-insulin autoantibodies. Anti-thyroperoxidase, anti-thyroglobulin, and anti-gastric parietal cell antibodies were also clearly positive. The case emphasized that new onset diabetic ketoacidosis, hypothyroidism, and cobalamin deficiency may simultaneously occur, and one disease can mask the features of the other, thereby making diagnosis difficult. It is noteworthy that an APS3 acute episode occurred in an asymptomatic elder woman for any autoimmune diseases.

Retrospective study on cost distribution of antiretroviral therapy in a tertiary care hospital

Background: Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV), which is an RNA virus. The first case of AIDS in human beings was reported in 1981, and now spread of HIV infection is alarmingly high with around 20 million deaths. The objective of the study was to determine the cost distribution of antiretroviral therapy among autoimmune deficiency syndrome (AIDS) patient attending the anti-retroviral therapy (ART) center of the tertiary care center.Methods: The objective of the study was to determine the cost distribution of antiretroviral therapy among AIDS patient attending the ART center of the tertiary care center. The study was retrospective, 20 patients included in different age groups and categories the cost incurred toward patients were divided under different heads: medication, laboratory diagnosis, transport, and miscellaneous costs.Results: It was found that major part of the cost is spent on drugs. The cost of transport and lab diagnosis varied based on age and stage of the disease. Miscellaneous costs were also high and were proportional to other costs.Conclusion: HIV infected population is more likely to have a lower socioeconomic status which has varied effect on the effectiveness of highly active ART. Some of the problems faced by them are access to health care, transport, economic instability, etc. all these factors have an impact on outcome of treatment. Overall it can be found that preventive measure than treating has better impact on quality of life.

Neural Control of Energy Expenditure.

The continuous rise in obesity is a major concern for future healthcare management. Many strategies to control body weight focus on a permanent modification of food intake with limited success in the long term. Metabolism or energy expenditure is the other side of the coin for the regulation of body weight, and strategies to enhance energy expenditure are a current focus for obesity treatment, especially since the (re)-discovery of the energy depleting brown adipose tissue in adult humans. Conversely, several human illnesses like neurodegenerative diseases, cancer, or autoimmune deficiency syndrome suffer from increased energy expenditure and severe weight loss. Thus, strategies to modulate energy expenditure to target weight gain or loss would improve life expectancies and quality of life in many human patients. The aim of this book chapter is to give an overview of our current understanding and recent progress in energy expenditure control with specific emphasis on central control mechanisms.

Etiology of primary ovarian insufficiency in a series young girls presenting at a pediatric endocrinology center.

The cause of the primary ovarian insufficiency (POI) remains unknown in the majority of cases. A retrospective study was carried out in 17 girls with POI and normal 46,XX karyotype evaluated before 20 years of age. The etiology of POI was determined in eight girls (group 1) and remained idiopathic in nine girls (group 2). In group 1, five patients had a medical history: cerebellar ataxia due to congenital disorder of glycosylation (CDG) 1 in three cases, mitochondrial disease in one case, and autoimmune deficiencies in one case. The diagnosis of POI was made on pubertal delay or primary amenorrhea in these five patients, whilst the others presented with clitoral hypertrophy at birth or short stature and pubertal delay in two cases with NR5A1 mutation or with short stature and learning difficulties in one case with mitochondrial disease. In group 2, associated diseases were arthrogryposis malformative, gut, and bladder malformations and kidney failure or parieto-occipital tumor. The genes tested (NR5A1, BMP15, GDF9, and NOBOX) showed no mutation. The frequency of defined etiologies (47%) is high. This is probably because of the recruitment of the cases at the pediatric center, where other somatic anomalies can lead to the accurate determination of the etiology.

Updated features associated with type 1 gastric carcinoids patients: a single-center study

Objective. Data on clinical presentation and associated features of patients with type 1 gastric carcinoids (T1-GCs) are scanty. This study aimed to provide detailed data on a series of patients with T1-GCs. Material and Methods. Clinical, laboratory, endoscopic, and histological data were assessed from 31 T1-GCs patients (cross-sectional design), consecutively diagnosed in a tertiary center according to a standardized diagnostic protocol. T1-GCs were diagnosed at baseline or follow-up gastroscopy for atrophic gastritis in 74.2% and 25.8% of patients, respectively. Results. Seventy-one percent of T1-GC patients were female. Age ranged from 23 to 78 (median 58 years). T1-GCs were more frequently diagnosed between 40–49 years (35.5%) and 60–69 years (32.3%) (p = 0.0383). Thyroid disease was present in 54.8% (in 29% autoimmune). All 31 patients had either cobalamin or iron deficiency with or without anemia. Manifest pernicious anemia was present in 67.7% of patients and cobalamin deficiency without anemia in 9.7% patients. Iron deficiency anemia was present in 29% and iron deficiency without anemia in 12.9% of patients. In 48.4% of patients, T1-GCs appeared as polyps, which were single in all cases and had a median size of 4 mm (range 2–15 mm). In patients with polypoid T1-GCs, thyroid disease of autoimmune and nonautoimmune origin (p = 0.0181) was more frequently associated. Conclusion. This study shows that T1-GCs may be diagnosed at any age. Autoimmune features are frequently present as well as cobalamin and iron deficiency. The copresence of autoimmune diseases and micronutrient deficiencies should be accurately investigated, in particular in patients with polypoid T1-GCs.

Histoplasma capsulatum in New England: A Case Study

1. Lori-Ann Camara, MLS(ASCP)CM 1. St. Luke's Hospital, New Bedford, MA 02740 2. Katerina Miraglia, D.C., MLS(ASCP)CM 1. Department of Medical Laboratory Science, University of Massachusetts, Dartmouth, MA 02747-2300 3. Susan J. Leclair, Ph.D.[⇑][1] 1. Department of Medical Laboratory Science, University of Massachusetts, 285 Old Westport Road, Dartmouth, MA 1. Address for Correspondence: Susan J. Leclair, Ph.D., Department of Medical Laboratory Science, University of Massachusetts, 285 Old Westport Road, Dartmouth, MA 02747-2300, 508-999-8786, sleclair{at}umassd.edu Overview: A healthy adult experienced a necrotic lesion on her back. She developed a reduced appetite, profound weakness, and fever. Routine x-rays and CAT scans demonstrated bilateral hilar adenopathy and patchy infiltrates. During bronchoscopy, biopsies and cultures for bacteria and fungi were taken. Patient History: A 24-year-old female was admitted to the hospital after treatment by her primary care physician for a necrotic skin lesion on her back. She is a social worker in a large urban area in the Northeast quadrant of the country and recently returned from a vacation in Honduras where she experienced a “bite” on her back. Approximately 10 days after her return, she experienced generalized weakness, night sweats, chills and headaches. She also states that she has experienced a significant drop in appetite. She did not complain of any chest pain but commented about heaviness behind her sternum. Medical imaging confirmed the presence of abdominal and inguinal adenopathy. The only relevant family history included a parent with COPD due to smoking and a paternal uncle with sarcoidosis. Given the continued presence of a now necrotic lesion, her primary care physician initiated a course of doxycycline for a suspected rickettsial infection. The necrotic lesion resolved but the systemic symptoms persisted and, together with the imagining results, a bronchoscopy was justified. Relevant Medical History: The patient has been healthy although her childhood medical history includes bouts of asthma that diminished over time. She stated that she has not have an instance of asthma for at least 10… ABBREVIATIONS: COPD – Chronic Obstructive Pulmonary Disease, CBC – Complete Blood Count, BUN – Blood Urea Nitrogen, EBV – Epstein Barr Virus, CMV – Cytomegalovirus, AIDS – Autoimmune Deficiency Syndrome [1]: #corresp-1

Stroke Literature Synopses: Basic Science

<i>Stroke</i> Literature Synopses: Basic Science

Utilization Of ADAMTS13 Testing In Suspected Thrombotic Thrombocytopenic Purpura (TTP)

IntroductionThrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening condition, characterized by thrombotic microangiopathy (TMA) that results in microangiopathic hemolytic anemia (MAHA), thrombocytopenia and clinical symptoms including altered mental status, renal impairment and fever. Diagnosing TTP in acute setting continues to be a challenge, since the clinical pentad is not consistently present in TTP, making it difficult to differentiate from other conditions with TMA. The initial clinical decision for plasma exchange (PEX) is supported if there are MAHA and thrombocytopenia without a clear alternative cause. Acquired autoimmune deficiency of ADAMTS13 is known to cause idiopathic TTP and forms a basis for success of PEX in many patients by replenishing ADAMTS13 in addition to immunosuppressive therapy. However, low levels of ADAMTS13 alone are known to be neither sufficiently sensitive nor specific for diagnosis of TTP in acute setting. The aims of this retrospective study were to evaluate: (i) the utilization of ADAMTS13 testing in suspected TTP; (ii) the utilization of PEX in patients with TTP diagnosis; (iii) the association of low ADAMTS13 activity with early mortality in TTP; and (iv) the incidence of ADAMTS13 deficiency in non-TTP diagnoses. MethodsAfter IRB approval, we identified 49 adult patients at a single tertiary medical center, who had ADAMTS13 testing between 2005 and June 2013 for suspected TTP. We searched the final diagnosis, either TTP or non-TTP. The results of ADAMTS13 testing and use of PEX were reviewed in the TTP and non-TTP patients. We identified the final diagnosis of the non-TTP patients. We assessed association of severely low ADAMTS13 activity (<10%) with early mortality defined as death within 3 months of diagnosis in patients with TTP diagnosis. ResultsOf the 49 patients who had ADAMTS13 testing 18 (37%) were male. The median age was 51years (range 20-81). All patients with TTP had PEX except one who could not initiate PEX due to early death. Twenty-five of the 30 patients (83%) with TTP had low ADAMTS13 activity and 17 of the 30 patients (57%) had severe deficiency (<10%). Five of the 30 patients with TTP suffered early mortality. The relative risk of death among TTP patients with severely low ADAMTS13 activity (<10%) was 1.15 (95% CI 0.22-5.90) compared to TTP patients with low to normal ADAMTS13 activity. Nineteen of the 49 patients who had ADAMTS13 testing subsequently had non-TTP diagnosis. Eight of these 19 patients with non-TTP diagnoses were found to have low ADAMTS13 activity: two patients with DIC secondary to sepsis; two patients with thrombocytopenia associated with primary presentation of hemophagocytic lymphohistiocytosis (HLH); one patient each with malignancy associated with TMA, vasculitis due to autoimmune disease, hematopoietic stem cell transplantation associated TMA and sepsis with renal failure; None of the eight patients with non-TTP diagnosis had severe deficiency. Four patients with non-TTP diagnosis underwent PEX and all had normal ADAMTS13 activity. Three of the 4 patients were subsequently diagnosed with drug induced TMA after oral opioid injection and one with hemolytic uremic syndrome. ConclusionsPatients with a strong suspicion of TTP should be treated with PEX. ADAMTS13 activity is found to be relatively specific for TTP, being supportive of the clinical diagnosis in majority of cases. There was no statistically significant correlation between death and severely low ADAMTS13 activity in the cohort of TTP patients studied. ADAMTS13 activity can be low in a variety of non-TTP conditions. Its utility in diagnosis and prognosis of non-TTP conditions, especially HLH, needs further evaluation. Disclosures:No relevant conflicts of interest to declare.

Cost effective improvement in the protocol for detection of haemoglobin variants –a step forward in quality assurance

BackgroundWe report the results of a cost effective improvement in the protocol for detection of haemoglobin variants which incorporates the findings of peripheral blood film along with the results of HPLC.FindingsA total of n = 10,844 samples were received from January 2011 till August 2011. Diagnosis of haemoglobinopathy was made in n = 1123 samples while other abnormalities included iron deficiency anaemia, megaloblastic anaemia, malarial parasite, autoimmune haemolytic anaemia and G6PD deficiency (n = 2473).ConclusionWe diagnosed 23% of abnormalities other than haemoglobinopathy by reviewing peripheral smear of samples received for detection of haemoglobin variants. This resulted in providing proper diagnosis to the referring physician without increment in cost.

Anti-cytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a recessive disorder resulting from mutations in the autoimmune regulator (AIRE). The patients' autoantibodies recognize not only multiple organ-specific targets, but also many type I interferons (IFNs) and most T helper type 17 (Th17) cell-associated cytokines, whose biological actions they neutralize in vitro. These anti-cytokine autoantibodies are highly disease-specific: otherwise, they have been found only in patients with thymomas, tumours of thymic epithelial cells that fail to express AIRE. Moreover, autoantibodies against Th17 cell-associated cytokines correlate with chronic mucocutaneous candidiasis in both syndromes. Here, we demonstrate that the immunoglobulin (Ig)Gs but not the IgAs in APECED sera are responsible for neutralizing IFN-ω, IFN-α2a, interleukin (IL)-17A and IL-22. Their dominant subclasses proved to be IgG1 and, surprisingly, IgG4 without IgE, possibly implicating regulatory T cell responses and/or epithelia in their initiation in these AIRE-deficiency states. The epitopes on IL-22 and IFN-α2a appeared mainly conformational. We also found mainly IgG1 neutralizing autoantibodies to IL-17A in aged AIRE-deficient BALB/c mice - the first report of any target shared by these human and murine AIRE-deficiency states. We conclude that autoimmunization against cytokines in AIRE deficiency is not simply a mere side effect of chronic mucosal Candida infection, but appears to be related more closely to disease initiation.

Risk factors for cervical dysplasia in AMINU kano Teaching Hospital

Background: Cancer of the cervix remains the commonest cancer of the female genital tract in developing countries. Ironically, it is preventable by a well established screening program. A study of the risk factors will be needed in order to determine the group of women among whom cervical cancer screening should be further emphasized.Objective: To determine the risk factors of dysplasia among a cohort of women in Aminu Kano Teaching Hospital, Kano Nigeria. Method: A cohort study of 550 women, who attended the gynaecological clinic of Aminu Kano Teaching Hospital, between January 2008 and December, 2010.Results: The period incidence for abnormal pap smears in this study was 11.6%. Age ≥ 35years and parity ≥ 5, age at coitarche, first marriage and first childbirth ≤ 18 years, multiple marriages, divorcees, low educational and socioeconomic statuses, family history of cervical cancer, previous history of excessive vaginal discharge, and Human Immunodeficiency Virus infection (HIV) /Autoimmune Deficiency Syndrome (AIDS) did confer some risk of dysplasia, while women in first order marriage, single, widows, use of hormonal contraception, intermenstrual vaginal bleeding, cigarette smoking, history of genital warts did not.Conclusion: These groups of high risk women should be encouraged to have mandatory cervical cancer screening 3 years after coitarche.

Early Diagnosis and Successful Treatment of Idiopathic Autoimmune Factor XIII Deficiency Complicated by Intracerebral Hemorrhage

Abstract 4634 Summary:Autoimmune factor XIII (FXIII) deficiency is an extremely rare bleeding disorder that can be life-threatening without prompt diagnosis and treatment. Many clinicians, even experienced hematologists, are unaware of this critical disorder. The causes and mechanisms of autoimmune FXIII deficiency remain unclear, but patients should be given top priority in receiving FXIII concentrate and immunosuppressive drugs when this is suspected to avoid fatal hemorrhage. We report the first Japanese case of autoimmune FXIII deficiency presenting as acute intracerebral hemorrhage. The clinical manifestations allowed prompt diagnosis and effective treatment in the form of emergency open drainage and infusion of FXIII concentrates combined with prednisolone therapy, leading to success in saving the life of this patient. Case:A 68-year-old man was hospitalized in another department of our hospital with abdominal pain and diffuse purpura of the abdominal skin in the absence of any history of trauma. He did not have a family history of bleeding tendency. Since he had been receiving low-dose aspirin because of a previous stroke, he received a transfusion of red cell concentrate and was discharged after cessation of aspirin. Two weeks later, he was taken to an emergency room with left hemiplegia. Computed tomography (CT) revealed an intracerebral hemorrhage measuring 4 cm in diameter. Sixteen hours after hospitalization, emergency open drainage was performed because of decreased levels of consciousness due to an expanding intracerebral hemorrhage measuring 7 cm with midline shift. Bleeding was controlled during the operation and CT showed no evidence of further bleeding after surgery. However, on postoperative day 2, subcutaneous bleeding spontaneously developed on the patient's head. Platelet counts and coagulation tests were normal, and other tests showed no evidence of factor VIII, factor IX or von Willebrand factor deficiencies. Given the lack of evidence of other autoimmune disorders or family history of bleeding tendency, we suspected idiopathic autoimmune FXIII deficiency and immediately initiated administration of FXIII concentrate. After treatment with FXIII concentrate, subcutaneous bleeding on the head was arrested and level of consciousness had recovered at all. 3 days after it was confirmed that FXIII activity was as low as 11%, and was not corrected by normal plasma at 1:1 in the cross-mixing test, suggesting the presence of anti-FXIII inhibitor and corroborating our clinical diagnosis. Based on the detection of anti-FXIII A autoantibodies in dot blot assay, we immediately started immunosuppressive therapy using prednisolone at 1 mg/kg combined with FXIII concentrate. Three weeks later, inhibition of FXIII activity was partly improved. FXIII activity was 36%, and 1:1 cross-mixing test was corrected, indicating that immunosuppressive therapy with prednisolone was proving successful. Four weeks later, his surgical wound had healed and FXIII concentration injection was discontinued. Prednisolone tapering was started, and after 8 weeks, with prednisolone tapered to 35 mg, FXIII activity was elevated to 53%. This was not yet sufficient, but anti-FXIII A subunit autoantibodies had disappeared completely, first as free-form antibody and then as bound/complexed antibody. Successful results were achieved in response to short-term treatment. In fact, in some of the 28 cases reported from Japan, anti-FXIII inhibitors were continued despite immunosuppressive therapy for a few years. The next target was to stop prednisolone therapy, because the major causes of death in patients with autoimmune FXIII deficiency is bleeding or infection. Why and when the patient developed autoantibodies remains unclear, as he had no evidence of other autoimmune disorders. This report describes a remarkably successful case in which early diagnosis and treatment of autoimmune FXIII deficiency achieved good outcomes for a case complicated by intracerebral hemorrhage. All clinicians should consider the possibility of this rare disease when they encounter patients who present with life-threatening bleeding and normal coagulation tests are inconclusive. Prompt diagnosis and treatment are crucial in saving the life of the patient. Disclosures:No relevant conflicts of interest to declare.

EEG and Seizure Manifestations of Cerebral Folate Deficiency

Researchers from Duke University Medical Center, Durham, NC report the EEG and seizure manifestations in 2 patients with folate receptor autoimmune antibody-mediated primary cerebral folate deficiency.