HLA-B Research Articles

HLA-B*57:01 genotype and Abacavir therapy: first report from genomic lab in AORN dei Colli Naples -Italy

AIDS (acquired immunodeficiency syndrome) is an infectious disease caused by the HIV virus (human immunodeficiency virus). The core of HIV treatment is antiretroviral therapy (ART). Abacavir, an antiretroviral drug used to treat HIV infections, is widely used in the treatment of HIV-supported infections. The active ingredient of the drug is not able to completely eradicate the infection, leading to a patient’s recovery, but it reduces the amount of virus in the body, keeping it at low levels. Pharmacogenetic tests are used in clinical practice to optimize the choice of medication or clinical management of the patient. Before starting treatment, it is necessary to perform a genetic exam to assess the presence of the HLA allele B57:01. Patients with the HLA B57:01 allele are therefore at increased risk of hypersensitivity to Abacavir. An adverse effect of abacavir is a hypersensitivity reaction, which can be severe and potentially life-threatening, and may limit treatment with the drug. The abacavir-induced hypersensitivity reaction was therefore associated with the presence of the class I allele of the major histocompatibility complex HLA-B*5701. Screening patients for HLA-B*57:01 before starting abacavir therapy reduces the incidence of hypersensitivity reactions. The study we carried out aims to evaluate the presence of the HLAB57:01 allele in the HIV-positive population present in our territory.

Immunodeficiency 70 (IMD 70)

Background: Immunodeficiency 70 is a rare disease and there are only very few cases in the literature. Case History: Young boy in his early 20’s from Indian subcontinent presented with recurrent episodes of fever, oral ulcers, loss of weight for past 3 years. Four episodes (july 2019, april 2020, APRIL 2021, Jan 2022) of fever, each high grade associated with chills, rigor, nausea, myalgia, throat pain, holo-cranial headache, painful oral ulcers over the tongue and painless over lips. Initial episode of fever was associated with leucopenia (3200) and thrombocytopenia (122000), acute kidney injury (creatinie-3.0) and pyelonephritis, transaminitis. He received 2 weeks of parenteral antibiotics and improved. Subsequent episodes of fever is not associated with any localizing symptoms or signs. No history Suggestive of connective tissue disease. Family history was non contributory. Physical examination: He was febrile (101 degree F), pulse rate 100/minute, respiratory rate 18/minute, tongue ulceration in lateral border, no lymphadenopathy, no organomegaly, normal sytemic examination. Evaluation: The patient was evaluated for chronic infections, hematalogical malignancy, Behcet’s disease, auto inflammatory syndromes like Haplo insufficiency of A20. His complete blood count, electrolytes, renal function test, liver function test urine microscopy, blood culture were normal. CRP was elevated (58 mg/l). Tzanck smear from buccal mucosa was negative. CT thorax and abdomen showed no significant lymphadenopathy, organomegaly, evidence of infections or malignancy. In view of oral ulcers & fever Behcet’s disease was considered and HLA b51 was sent and came negative. Exome genome sequencing was done to diagnose immunodeficiency or autoinflammatory syndromes which came positive for immunodeficiency 70. Treatment: He was treated with colchicine and fever subsided and leucopenia improved Discussion: Immunodeficiency-70 (IMD70) is an autosomal dominant immunologic disorder characterized by severe cutaneous warts on the hands, feet, and face, suggesting increased susceptibility to human papillomavirus (HPV) infection. Affected individuals may also have recurrent bacterial infections like pneumonia, boils, sinusitis, as well as feature of autoinflammation, such as colitis, celiac disease, and retinal vasculitis. Laboratory studies show decreased CD4+ T cells and decreased CD19+ B cells; hypogammaglobulinemia, combined T cell and B cell immunodeficiency characterized by decreased CD4+ T cells, decreased CD19+ B cells, recurrent bacterial infections, and severe cutaneous warts on the hands, feet, and face that has material basis in heterozygous mutation in IVNS1ABP on chromosome 1q25.3.

P215 Highly sensitized HLA B46 homozygous patient that makes antibodies to Bw4 and Bw6 public epitopes

P215 Highly sensitized HLA B46 homozygous patient that makes antibodies to Bw4 and Bw6 public epitopes

Long term disease-free survival in locoregional, metastatic and/or recurrent UCNT.

e18023 Background: Undifferentiated Carcinoma of Nasopharyngeal Type (UCNT) is a rare and aggressive type of head and neck cancer related to the Epstein Barr virus (EBV), genetic (HLA B5 in Algeria) and environmental factors. It is the most frequent histological variant of ENT cancers. It has geographically selective epidemiologic features unrelated to external carcinogens, and is known to be radiosensitive and chemosensitive. Methods: Seventy-one patients with biopsy-proven UCNT presenting to a single oncology unit between 2015 and 2022 were assessed for their long-term response to treatment. The sex ratio of cases was 3M: 1F; thirty-one patients (43%) were under the age of 50; 11 (15%) under the age of 35; and among these, there were two 19 year old males. The initial median World Health Organization (WHO) performance status was 1.6. These patients with locoregional (LR), recurrent (REC) and/or metastatic (MTS) UCNT were treated with monthly cycles of platinum-based chemotherapy of cisplatin (CDDP) 75 mg/m2 IV or Carboplatine AUC-4 and Docetaxel 75 mg/m2 IV followed by fluorouracil (5FU) 1000 mg/m2/day continuous IV infusion days 1 to 4 (TPF) in locally advanced disease, and with cisplatin (CDDP) 75 mg/m2 day 1 or Carboplatine AUC-5; and fluorouracil (5FU) 1000 mg/m2/d continuous IV infusion days 1 to 4 (PF) in recurrent and/or metastatic cases. The choice of systemic therapy was individualized based on patient characteristics including performance status, goals of therapy. Results: Those LR or MTS patients who were still alive without evidence of disease after 36+ months were categorized as complete responders (CRs). A subgroup of CRs was identified who had failed prior chemotherapy. MTS patients with less than three distant osseous sites underwent additional radiation therapy. Conclusions: Encouraging results for this particular type of head and neck cancer confirm the chemosensitivity of UCNT, and the observation of long-term responders makes curability a real consideration.

Immunogenetic parameters in children with atopic diseases

Objective. To determine the features of the distribution of antigens of the major histocompatibility complex in children of preschool and primary school age with atopic diseases.
 Materials and methods. Under observation there were children with a moderate course of the diseases such as atopic dermatitis, atopic dermatitis with concomitant persistent allergic rhinitis, independent persistent allergic rhinitis, atopic bronchial asthma. The patients were identified class I and class II antigens of HLA-complex.
 Results. The studies have shown that patients with atopic dermatitis had a high incidence of HLA B15, DRB1*13 and DQB1*0602-8: in patients suffering from atopic dermatitis with concomitant persistent allergic rhinitis HLA B12, B13 and DQB1 * 01; in patients with independent persistent allergic rhinitis HLA A10 and DQB1 * 201; in patients with atopic bronchial asthma HLA B18.
 Conclusions. Representation of these antigens of the HLA complex in the tissues was associated with an increase in the risk of atopic diseases by 2.34.6 times.

Evaluation of HLA-B51 frequency and its relationship with clinical findings in patients with Behçet’s disease: 4-year analysis in a single center

BackgroundThe clinical findings of Behçet’s disease (BD) differ according to the country and race investigated. The most important genetic factor known in the pathogenesis of BD is HLA-B51, and this positivity is high in countries on the “Silk Road” where BD is as frequent as it is in Turkey. Although the positivity of HLA B51 is proven to be high in Turkey, there are no studies in the area of the western Black sea demonstrating its relation to the demographic. We aimed to investigate the association of HLA-B51 positivity in Turkish patients diagnosed as having BD and the relationship between the demographic and clinical findings of the patients.ResultsIn this descriptive, cross-sectional study, a convenience sample of adults with BD was obtained from an outpatient clinic of a university hospital in Turkey between January 2018 and January 2022. Patients were diagnosed as having BD according to the criteria of the International BD Study Group, and the patients’ sociodemographic and clinical characteristics were recorded retrospectively. Demographic data and the frequency of clinical findings were compared between patients who were HLA-B51-positive and HLA-B51-negative. Sixty patients (55.6%) were HLA-B51-positive. Oral ulceration, genital ulceration, thrombophlebitis, and family history of BD were found to be higher in patients who were HLA-B51-positive. Erythema nodosum, papulopustular eruption, pathergy positivity, arthritis, and ocular involvement were less frequent in patients with HLA-B51 positivity. However, there were no statistically significant differences according to the frequency of clinical findings between the HLA-B51-positive and HLA-B51-negative groups.ConclusionsHLA B51 positivity is not diagnostic of BD; however, it may affect clinical phenotypes. Although oral and genital ulcerations, thrombophlebitis, and positive family history of BD were found to be common in patients with HLA-B51 positivity, this relationship could not reach statistical significance.

Clinical Manifestations of Behçet's Disease: A Retrospective Cross-Sectional Study.

Behçet's Disease (BD) is a systemic vasculitis, highly prevalent in Eastern Asia to Mediterranean countries. Iran is among the countries with the highest prevalence of BD, and previous studies in different countries have shown a broad range of clinical manifestations of the disease. The present study is conducted to evaluate the prevalence of the clinical manifestations of BD in patients referring to rheumatology clinics of two distinct referral hospitals in Tehran and Zanjan, Iran. In this retrospective, cross-sectional study, the medical records of patients with BD were reviewed, and age at onset, sex, the delay between the onset of symptoms and diagnosis, clinical manifestations, HLA B27, HLA B51, HLA B5, haematuria, proteinuria, leukocyturia, Erythrocyte Sedimentation Rate (ESR), and pathergy phenomenon were included in the study. The collected data were analysed by χ2 test using SPSS 23. A total of 188 patients (Male/female ratio = 1.47) were included in the study with mean ± SD age at onset of 27.98 ± 10.47 years and a mean ± SD of delay between the onset of symptom and diagnosis of 5.70 ± 7.16 years. The most common clinical manifestation was mucosal involvement (85.1%), followed by the ocular lesion (55.3%) and skin manifestations (44.7%). The Pathergy phenomenon was observed in 98 patients (52.1%). Moreover, 45.2% had positive HLA B5, followed by HLA B51 (35.1%) and HLA B27 (12.2%). This study demonstrated that male/female ratio and mean age at onset were comparable to the results of previous studies in Iran. Significant associations between HLAB5 and clinical manifestations underline the pivotal role of genetic factors in BD.

Behcet Disease- A Clinical Entity Requiring A Very High Grade Of Clinical Suspicion

Introduction - Behcet disease is an auto-inflammatory systemic vasculitis. It usually comprises a triad of recurrent oral and genital ulcerations, ocular manifestations. Case Report- A18 years old lady presented with recurrent oral ulceration since 1 year which was causing difficulty in chewing food and burning sensation in oral cavity. Out of high grade of clinical suspicion, due to the recurrent nature of ulcers and rapid resolution by steroids, HLA profiling was done, and HLA B5 came out to be positive and the patient was diagnosed as Behcet disease. Conclusion- Behcet disease has a multi-systemic involvement. The diagnosis of Behcet disease requires a very high threshold of clinical suspicion to appropriately manage the disease. Key words: Behcet Disease, HLA B5, Aphthous ulcer, Oral steroids

HLA class I and class II antigens in sarcoidosis.

Sarcoidosis is a multisystem granulomatous disorder. Its exact cause is unknown, but it is believed that an external agent may cause the characteristic immune reaction in genetically susceptible individuals. There is therefore general recognition that genetic vulnerability to sarcoidosis is one of the potential risk factors. HLA is encoded by genes in the major histocompatibility complex on chromosome 6. These surface cells are important in presentation of antigen and play a key part in the body's immune response to external antigens. Various HLA subtypes are more common in people with sarcoidosis than in those without. Variances in vulnerability, presentation,progression and prognosis have been related to different HLA phenotypes. HLA genes offer information into the factors driving sarcoidosis and prognosticating tools. However, in Africa, including South Africa (SA), there are no data on HLA types in relation to sarcoidosis. To determine HLA class I and II associations in SA sarcoidosis patients. Phenotype frequencies of HLA-A, B and C and DQB1 and DRB1 were calculated for 51 consecutive patients with biopsy-proven sarcoidosis attending the respiratory clinic at Charlotte Maxeke Johannesburg Academic Hospital and 63 controls, who were potential organ donors. The frequencies of the tested HLA loci were determined by direct counting. The significance of the associations between the various loci tested for and the presence or absence of sarcoidosis was estimated from 2 × 2 tables using the χ2 test. Of the 51 patients, 70.6% were female. The mean age was 44.6 years. Analysis of HLA class I and class II phenotypes in sarcoidosis patients revealed a significant association with HLA-B15, C4, C7, C12, C15, C16, C17, DQ3, DR8 and DR11. In addition, a significant negative (protective) association with HLA A9, A28, B12, B17 and DR2 was observed. This HLA study in SA patients suggests that genetic factors play a role in the causation of sarcoidosis. Some HLA subtypes have a significant association with sarcoidosis in SA patients, while other subtypes may be protective. The study supported the association of HLA antigens with sarcoidosis and implies that there is a genetic predisposition to sarcoidosis in the SA population.

Primary sclerosing cholangitis-A long night's journey into day.

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57 Ocular tuberculosis: a differential for chronic panuveitis

Background Mycobacterium tuberculosis is an organism responsible for causing chronic granulomatous inflammation leading to active or latent tuberculosis (TB). Both pulmonary and extrapulmonary infections; including the skin, the eye, the cardiovascular, genitourinary and gastrointestinal systems can occur. Within the eye, it can cause global disease ranging from anterior or posterior uveitis to retinal TB. Within this abstract we demonstrate a case of chronic panuveitis with a diagnosis of ocular TB.MethodologyRetrospective chart reviewResultsWe reviewed a 9-year-old- male in the rheumatology outpatient clinic who was on treatment for ocular TB with methotrexate 2.5 mg once a week, prednisone 5 mg once a day, maxitrol eye drops once a day and prednisolone eye drops twice a day.He presented with a red, painless left eye with deteriorating vision 2 years ago. Functional enquiry was unremarkable. He was noted to have a fixed dilated left pupil at 3-4mm but other examinations were normal. Extensive investigations were carried out, including an Interferon-gamma release assay (IGRA)- which was positive. Toxoplasma antibody test, Treponema pallidum Haemagglutination test, and chest X-ray were all negative. He was then started on the above-mentioned therapies with marked improvement.A decision on increasing the methotrexate dose if steroid tapering showed no improvement was undertaken and a plan on reassessing the patient with ANA, ACE and HLA B51 was made, to ensure complete workup.Discussion and conclusionIntra or extra ocular TB (OTB) manifestations may result as a direct inoculation of the organism in ocular fluid or as a systemic immune response initiated by an infection from a distant site. There is a myriad of ocular manifestations of OTB which make forming a clinical diagnostic criterion difficult. The gold standard for diagnosis is an ocular fluid culture showing organisms but the yield may be low and the risk of damage to surrounding structures may be high. PCR tests done on the sample may yield clinical information but non ocular tests, such as the IGRA and tuberculin tests may also be employed. Therapy depends on active vs latent disease and mainly involves anti-inflammatory agents and anti-TBs.Ocular TB may lead to sudden and irreversible blindness with high socioeconomic implications and hence, an index of suspicion in areas with a high disease burden should be kept as diagnosis poses a challenge.

87 Intracerebral inflammatory pseudotumor in Behçet’s disease: a pediatric case report

IntroductionBehçet's disease is a chronic, relapsing, multisystem vasculitis. The diagnosis is essentially clinical, due to the absence of specific biological criteria, which remains very difficult to establish in pediatric age because of often insidious or atypical disease onset. The association of Pseudo Inflammatory Non-Specific Tumors (PTINS) and Behcet's disease (BD) is exceptionally reported. We report the case of a 12-year-old boy with Behçet's disease who presented with an inflammatory pseudotumor during the course of his disease.Methods and resultsA 12-year-old boy, from Batna (Algeria), with no relevant past medical history, admitted in 2010 for the management of a venous thrombosis of the right lower limb without any obvious cause and which responded well to anticoagulant treatment.A year later, the child was readmitted for polymorphic clinical signs made up of joint damage (inflammatory arthralgia of the large joints), digestive (glairo-bloody diarrhea) and ocular (decreased visual acuity) and skin and mucous membranes (oral-genital apthosis and erythema nodosum of the 4 limbs).Lab work-up showed significant inflammatory syndrome with erythrocyte sedimentation rate (ESR) of 100 mm at the first h, C-reactive protein (CRP) up to 400 mg/l and thrombocytosis (700 000–900 000 elements/mm2). HLA B51 was negative.The patient was treated with Colchicine, Steroids, and Aspirin with partial response. Subsequently, a treatment with azathioprine was started, with clinical improvement (despite occasional digestive crises) but with persistent biologic inflammation.In 2012 the patient presented with a unilateral decrease in visual acuity. A CT scan was performed showing an intracranial tumor compressing the right optic nerve with all the criteria of a malignant tumor (rupture of the cortex, increase in volume on 2 successive CT scans). A transsphenoidal biopsy of the mass revealed a non-specific inflammation. Biological treatment with anti-TNF alpha (Infliximab) was associated with a spectacular tumor regression, allowing retrospectively the diagnosis of an inflammatory granulomatous lesion related to Behçet's disease rather than a malignant tumor. The outcomes were favorable with clinical and biological improvement for the first time since the onset of the disease.ConclusionBehcet is rare in the pediatric age group and it is difficult to diagnose. Nonspecific inflammatory pseudotumors can be associated with Behçet's disease and constitute a real diagnostic and therapeutic challenge.Disclosure of InterestNone declared

58 Comparison of the 2015 pediatric diagnostic criteria for Behcet’s disease with the 2014 and 1990 International Study Group Diagnostic Criteria

BackgroundBehçet's disease is a multisystem vasculitis whose pathogenesis remains unclear. Although usually described in young adults, it may begin in childhood. The diagnosis is clinical, based on international criteria. The limitations of early diagnosis are related to the progressive onset of symptoms and the variety of differential diagnoses at this age in the absence of a pathognomonic diagnostic test.ObjectivesTo report the epidemiological features of our series and to compare the 2015 pediatric criteria with the 2014 and 1990 international criteria.Materials and MethodsThis is a monocentric, retrospective study of 31 children over an 11-year period from January 2011 to December 2021. All patients suspected with Behcet's disease by a pediatric rheumatologist were included in the study, the 2014 international criteria “ISG 2014” being the gold standard classification criteria used in our center.Results31 cases of Behcet's were collected. The mean age was 10 years (5.5–16) ± 2.87 years. A female predominance is noted with a sex ratio F/M of 1.21. A quarter of the patients were from a consanguineous marriage and 38.7% had a family history of Behcet disease. Mucocutaneous manifestations were represented by recurrent oral aphthosis 87.1%, genital aphthosis 29%, pseudofolliculitis 48.4%, erythema nodosum 6.5% and acne lesions 3.2%. The pathergy test was positive in 1 case. Ocular involvement was reported in 29% and joint involvement in 45.2%. Thromboembolic complication was seen in 9.6% and neurobehcet in one patient. The HLA B51 antigen was present in 45.2% of cases. In our series 38.7% respond the pediatric criteria, while 61.3% met the 2014 international criteria and 35.5% met the 1990 international criteria. The 2015 pediatric criteria have respectively a sensitivity and specificity of 63.2% and 100% (p = 0.002) compared with the 2014 international criteria taken as gold standard, as well as the 1990 international criteria with a respective sensitivity and specificity of 52.6% and 91.7% (p = 0.034).ConclusionOur study highlights a female predominance, a high rate of consanguinity and familial Behcet. The sensitivity and specificity of the 1990 pediatric and international criteria appear to be better than those of 2014, with a more significant trend for the 2015 pediatric criteria (p = 0.002).

S2789 A Rare Triad of Ulcerative Colitis, Large Vessel Vasculitis and Celiac Disease

Introduction: Inflammatory bowel disease (IBD) has been associated with large-vessel vasculitis (LVV), with the diagnosis of IBD preceding that of LVV by years. We present for the first time in known literature a triad of concurrent ulcerative colitis (UC), aortitis and celiac disease. Case Description/Methods: A 58 year old Hispanic man with a history of hypertension and gout presented with two weeks of intractable temporomandibular headaches, and two months of non-bloody diarrhea and weight loss. Physical exam was unremarkable. Labs showed hemoglobin 6.9 g/dL, erythrocyte sedimentation rate 120 mm/hr, C-reactive protein 281 mg/dL and IgA tissue transglutaminase antibody 23 U/mL. ANA, C3, C4, proteinase-3 and myeloperoxidase antibodies were within normal limits. Colonoscopy showed pancolitis from rectum to ascending colon. The terminal ileum was normal. Abdominal MRI found aortic wall hyperintensity from the renal arteries to common iliac bifurcation. CT angiogram showed wall thickening of the left carotid artery, aortic arch, descending thoracic and abdominal aorta, consistent with vasculitis. Patient was given stress dose steroids with improvement in headache and normalization of ESR and CRP. Temporal artery biopsy was unremarkable. Four months after hospitalization, repeat colonoscopy with duodenal biopsies for celiac disease revealed mild increase in intraepithelial lymphocytes with preserved villous architecture. He was started on a gluten free diet and adalimumab in combination with methotrexate for UC and LVV. Discussion: About 10 case reports of patients with both UC and either Takayasu (TAK) or giant cell arteritis (GCA) have been described, with UC typically diagnosed 15-45 years before the vasculitis. Vasculitis in the GI tract can mimic IBD, making colonoscopy and biopsy crucial for diagnosis. HLA haplotypes A24, B52, and DR2 are associated with both UC and aortitis and Interleukin-9, observed in temporal arteritis lesions, may be implicated in the pathogenesis of UC. Shared chromosomal variants between patients with UC and celiac disease may explain why IBD risk is up to 9-fold higher in patients with celiac disease. Our patient may have presented with isolated aortitis or an early form of GCA. Methotrexate is used to treat LVV and is combined with an anti-TNF agent to treat UC, as in our case. This is the first known report of co-occurring UC, celiac disease and aortitis; however, whether the three inflammatory conditions are mechanistically related warrants further research.

Behcet’s disease (Silk Road disease): a rare inflammatory disease

Background: Behcet’s disease (Silk Road disease), a rare immune-mediated multisystem inflammatory disorder described by intermittent oralaphthae and genital ulcer, backsliding uveitis, mucocutaneous, articular, gastrointestinal, neurological and vascular manifestations, with no cure.It is brought about by changes in the: a) arteries that flexibly blood to the body tissues b) veins that return the blood to the lungs, the rear of the eyes retina, brain, joints, skin and bowels.
 Case Presentation: A 55-year-old male patient was sensed with c/o joint agony in lower appendages, oral ulcer and scrotal ulcer. On physical assessment the patient was cognizant and oriented with B/L lower leg joint emanation. All lab examination including RA factor was within normal limits, with diminished Serum Vitamin D. HLA B51, ANA were checked and oral mucosal biopsy was done. The most punctual sign exhibited was oral disintegration, various shallow ulcer and scarcely any dissolved knobs in the scrotum. At that point the patient gave joint pain and numbness on right leg. On neurological assessment, a strange motor nerve conduction saw with right tibial neuropathy. At first, doubt with syphilis and tarsal tunnel disorder and following 7-8 days of affirmation, analyzed as Behcet's illness dependent on dermatological, rheumatologic and neurological signs. Treatment given was symptomatic and supportive with pain relievers, corticosteroid, antibiotics, IV fluids, PPI, vitamin supplement, laxative and local anaesthetic.
 Discussion:Without adequate data it's difficult to examine, in light of anomaly and standardized treatment are questionable at present. New information with respect to its immunopathogenesis, genetics will significantly help in the advancement of research center tests, diagnostic criteria and particularly in the decision of the best treatment

P048 Metastatic Crohn's Disease Debuting with Severe Oral Manifestation and Vulvar Involvement - A Diagnostic Challenge.

Background: Metastatic Crohn's disease (MCD) is an unusual cutaneous manifestation in Crohn's disease (CD), and concomitant oral and vulvar involvement is even more unusual. It can debut with cavity lesions oral such as canker sores, ulcers, lip edema, granulomatosis, dry mouth, abscesses in the salivary ducts, erythema, gingivitis, glossitis, among others, however, simultaneous compromise with several oral lesions and so severe with loss of multiple pieces dental is very rare. Patient in the fourth decade of life with a family history of autoimmunity who debuts with severe oral manifestations with a requirement for extraction of 14 teeth, severe gingivitis, smooth tongue and glossitis, aphthous stomatitis, ulcers, lip edema and angular cheilitis, without clear cause, and in management by the oral pathology group. Associated with this, there was vulvo-perineal compromise with ulcerated, inflammatory, erythematous and infiltrated lesions. It was initially suspected of Behçet's disease, HLA B51 was performed, it was negative, also, negative pathergy test, and no other suggestive systemic findings. A vulvar biopsy was performed with marked edema of the dermis, dilated lymphatics with perivascular and interstitial lymphoplasmacytic infiltrate and noncaseating granulomas, negative for microorganisms. At this level, it was compatible with MCD, without presence of gastrointestinal symptoms and calprotectin levels in stool in normal range. High and low endoscopic studies and capsule endoscopy were performed in small intestine, without alterations, it was managed by dermatology with topical steroids and by dentistry with dental implants. It was considered patient with inflammatory bowel disease (IBD) type CD with severe extraintestinal manifestations (EIM), although it did not present compromise intestinal treatment, it was decided to start treatment with anti-TNF initially with adalimumab developing paradoxical psoriasis, later treatment with infliximab, again with presentation of severe paradoxical psoriasis, for which it was suspended. Cyclosporine was also used as an immunomodulator, presenting intolerable tachycardia. 18 months after these symptoms, she presented episcleritis of the left eye and begins with colicky abdominal pain and average diarrheal stools 5-a-day, it was performed high and low endoscopic studies without alterations and new capsule endoscopic of small intestine documenting Crohn's enteritis involving the duodenum, jejunum and ileum, considering a patient with IBD type CD, with EIM with vulvo-perineal compromise, severe oral involvement and episcleritis. Currently is under management with azathioprine and Ustekinumab, with clinical improvement significant. MCD represents a diagnostic challenge, it can debut without gastrointestinal involvement, and its clinical and histopathological findings simulate other entities. A timely diagnosis is required to seek early benefit in the patient.

Unusual Presentation of PLA2G6-Related Neurodegeneration with Retinal Vasculitis.

Unusual Presentation of PLA2G6-Related Neurodegeneration with Retinal Vasculitis.

P012 An HLA Typing for every JIA?

Abstract Background Among the genetic susceptibility factors of Juvenile Idiopathic Arthritis (JIA), the HLA class I and II genes are the most frequently involved. These HLA genes are extensively investigated, highlighting the role of self/non-self-balance in auto-immune and auto-inflammatory diseases. Methods We carried out a retrospective study of HLA class I and/or class II genes (HLA B and HLA DR genes) of 12 children. Genotyping was performed through microlymphocytotoxicity for class I (HLA B5 and B27) and through indirect immunofluorescence and PCR for class II (HLA DR4) Results The summarized results depict: 4 patients have the HLA B27 + 3 patients have the HLA B5+ 1 patient had the HLA DR JIA comprises a broad spectrum influenced by both genetic and environmental factors. The International League of Rheumatology Associations (ILAR) has defined seven categories of JIA consisting of a myriad of pediatric auto-immune and auto-inflammatory diseases. The HLA genomic region is also associated with a wide range of auto-immune diseases, encoding the HLA-DR, HLA-DQ, and HLA-DP proteins involved in the peptide’s presentations to HLA -class II-restricted CD4 + helper T cells. These mechanisms are involved in the pathogenesis of various diseases such as rheumatoid arthritis. Juvenile arthritis has also been associated with a single nucleotide polymorphism in the regulatory region of the interleukin-6 gene, close to the HLA coding region. Conclusion Genetic exploration of the HLA system in JIA, more accessible and less expensive than other targeted genetic typing, can be a helpful tool. Its usage ought to be encouraged and expanded in clinical practice.

Immunodynamics of Paroxysmal Nocturnal Hemoglobinuria

In the context of immune-mediated attack in aplastic anemia (AA), PIGA mutations produce a clonally-restricted escape phenotype in an attempt to restore hematopoiesis. Along with PIGA lesions, HLA class I/II mutations may represent an alternative way to render cytotoxic T cell recognition less effective. Microdeletions of 6p21, uniparental disomy [UPD] of 6p and mutations of HLA genes have been previously identified in AA patients. One could stipulate that paroxysmal nocturnal hemoglobinuria (PNH) may be an alternative mode of clonal evolution as opposed to HLA mutation acquisition or instead be a redundant pathway of immune escape co-existing with such lesions. Here, we took advantage of a large cohort (n=92) of patients with hemolytic PNH (granulocytes clone size >20% and LDH>x2.5 ULN) to elucidate the immunodynamics of PIGA/HLA clone(s) (Fig1A).We first used a deep targeted sequencing panel covering HLA classical loci and applied an in-house newly developed pipeline on 62 patients with PNH. Overall, 35% of cases had HLA alterations, which were found at a similar rate in patients studied at onset (33%) and during the course of the disease (32%). These alterations were classified as allelic losses in 15% of cases while majority of mutations were missense (57%) followed by 5‘ or 3‘ UTR (20%), nonsense (15%) and frameshifts (8%) with a median variant allelic frequency (VAF) of 5% (range, 2-95). Of note, the canonical exon 1 HLA B14:02 mutation (c.19C>T, p.R7X) 1,2was found in 2 patients who both had de novo PNH with a granulocyte clone size of 60% at disease onset (Fig1B).To clarify whether the PNH phenotype conveys an absolute resistance from immune attack, one should determine whether in these patients HLA mutations arise indeed within non-PNH cells. Consequently, we also performed HLA sequencing on 9 patients whose samples (n=18) were previously sorted by flow cytometry to enrich for CD59+ and CD59- fractions. HLA mutations were identified in both CD59+ and CD59- fractions at similar rates (44% each) and VAF (5% vs 3%, p=0.3) while no “canonical” exon 1 mutation was found.When looking at associations with disease-specific characteristics, we did not identify any significant differences in terms of burden of HLA events and disease ontogeny (primary vs secondary to AA cases) as well as baseline demographics characteristics (gender, age at presentation), dominant erythrocytes type (II vs III), and thrombotic events. No correlations with specific types of PIGA mutations nor their burden were found in HLA-mutated vs non-mutated groups as also confirmed by the absence of relationship with PNH granulocyte clone size (62% vs 72%, p=0.5). Of note, in HLA mutants the VAFs of HLA lesions were significantly lower than those of PIGA (5% vs 18%, p<0.001) underlying their possible less powerful role in driving immune escape within the context of AA overshooting reactions. To validate these results, we have designed a highly quantitative flow cytometric method for detection of HLA expression (A, B, C for class I; DQ, DR, DP for class II) on CD59+ vs CD59- fractions of CD34+ and CD15+ cells obtained from PNH patients. Preliminary results in 7 patients showed a general downregulation of HLA expression within PNH clones (delta HLA MFI of CD59+ vs CD59- fractions), consistent with our ability to detect HLA mutations also in PNH cells (Fig1C). This preferential down-modulation on PNH cells suggests a possible selection mechanism operating agonistically and in a non-mutually exclusive fashion with the PNH-intrinsic privilege. Moreover, these findings may also represent a byproduct of antigen processing machinery impairment due to proteasomal accumulation of proteins, which would have been GPI-linked and exported to the membrane.In sum, our study indicates that PNH phenotype conveyed by PIGA mutations operates independently from HLA mutations as means of immune escape. In addition, based on these results we stipulate that HLA down-modulation via various mechanisms is operative in the context of the PNH phenotype and the immune privilege of PIGA clones is not absolutely protective. Patients with PNH may have elements of immune suppression. In fact, their responses in the context of reduced-intensity transplant do eliminate hosts PNH clones following transplantation. 3 [Display omitted] DisclosuresPatel: Alexion: Consultancy, Other: educational talks, Speakers Bureau; Apellis: Consultancy, Other: educational talks, Speakers Bureau. Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Novartis: Consultancy; Alexion: Consultancy; Regeneron: Consultancy.

Early Administration of Partially HLA Matched Third Party Virus-Specific T-Cells in Conjunction with Antiviral Treatment for Initial Viral Infection after Allogeneic Stem Cell Transplant Is Safe and Leads to High Rates of Viral Control

Introduction:Reactivation of viruses such as cytomegalovirus (CMV) or Epstein Barr virus (EBV) after allogeneic hemopoietic stem cell transplant (aHSCT) is associated with increased non relapse mortality and a requirement for antivirals with mainly hemopoietic and renal toxicities that can further compromise transplant outcomes and increase health care costs. The use of 3 rd party virus specific T cells (VSTs) has been effective in treating recurrent and refractory viral reactivation after transplant and leads to rapid restoration of viral immunity. We investigated whether early administration of 3 rd party VSTs together with antiviral therapy could safely enhance immune recovery and improve viral control in patients requiring treatment for their initial CMV and EBV infection after aHSCT.Methods:We performed a single arm phase 1 clinical trial in which aHSCT patients requiring treatment for their first CMV or EBV reactivation (or EBV driven malignancy) received infusions of partially HLA matched 3 rd party VSTs within 7 days of commencing standard antiviral treatment. Patients were required to have a viral copy number of at least 1,000 copies/mL for CMV, 10,000 copies/mL of blood for EBV, or proven tissue infection irrespective of copy number for treatment initiation. T cell products were expanded from G-CSF stimulated aphereses from normal donors following peptide stimulation and CD137 magnetic bead selection. T cells were cultured for up to 12 days before specificity testing and cryopreservation. Patients were eligible to receive up to 4 doses of VSTs at 4 week intervals with products selected with a minimum of 1 of 6 HLA matches at HLA-A, -B and -DRB1 with antiviral activity demonstrated through the shared HLA molecule. The primary endpoint of the study was infusion safety.Results:Thirty aHSCT patients were treated with 1-4 VST infusions (27 CMV, 3 EBV) commencing at a median of 4 days after initiation of antiviral treatment. 27 patients were transplanted for hematological malignancies, 3 for immune deficiencies. Conditioning was myeloablative in 12 patients and the majority of patients (22/30) received in vivo T cell depletion. 7/27 CMV seropositive recipients were transplanted from CMV seronegative donors. A total of 41 infusions were given, most frequently targeting antigens presented through shared HLA molecules A2 and/or B7. All infusions were administered at a cell dose of 2 x 10 7/m 2. VST products were CD3 + (median 97.9%, range 96.2 - 99.4%), with median percentage of CD3 +CD8 + 85.8% (range 23.2 - 95.5%). There was one infusion related adverse event consisting of fever that resolved rapidly after admission and antibiotics. Overall viral response rate was 100% with a complete response rate of 94% (Figure 1). Of the 28 patients who achieved a CR (after either 1 or 2 infusions), 22 remained virus PCR negative (n = 8) or below the limit of quantitation (n = 14) for the duration of follow up. 3 patients had brief episodes of quantifiable reactivation not requiring additional therapy and 3 patients required a second infusion following initial CR. All remained PCR negative after their 2 nd CR. All 3 patients treated for EBV PTLD achieved sustained CR. Overall rates of acute and chronic GVHD post-infusion were 33% (10/30) and 20% (6/30) respectively (grade IIII/IV aGVHD 10%, severe cGVHD 7%). VST infusion was associated with a reduction in activation and inhibitory marker expression on CD4 + and CD8 + lymphocytes within the first 30 days and recovery of CD8 + (and more slowly CD4 +) CD45RA -CD62L - effector memory cells. Within the first 100 days after infusion there was an increase in interferon-γ responsiveness of blood lymphocytes. CMV and EBV specific tetramer positive T cells were detected comprising up to 13% of CD8 + cells for up to 6 months post infusion. At 1 year post transplant, non relapse mortality was 10%, cumulative incidence of relapse was 7% and overall survival was 87%.Conclusion:The combination of traditional antiviral treatment and early administration of 3 rd party VSTs is safe and achieves high rates of viral control without evidence of increased acute or chronic GVHD and with evidence of enhanced immune responses to viral antigens. 1 year overall survival was high with low rates of non relapse mortality and relapse. These encouraging results require confirmation in a prospective randomized study comparing best available therapy with best available therapy combined with early VST administration. [Display omitted] DisclosuresRitchie: Novartis: Honoraria; BMS: Research Funding; Takeda: Research Funding; CRISPR Therapeutics: Research Funding; Amgen Inc: Honoraria, Research Funding; CSL: Honoraria.