IgG2 Deficiency Research Articles

Pathology Quiz Case 2

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Antibody deficiency in adults with 22q11.2 deletion syndrome

There are limited data on immunological disorders, infection profile, and autoimmunity among adults with the 22q11.2 deletion syndrome (22q11.2DS) in the literature. To expand this knowledge base, we evaluated immunoglobulin levels, lymphocyte subsets, and T-cell function in 26 adults, consecutively referred to our 22q11.2DS multidisciplinary team. Their medical records were also reviewed with respect to frequency and severity of infections and autoimmune disorders. Six patients had low immunoglobulin levels; among these patients, one had a combined IgA and IgG1 deficiency, one had an isolated IgG3 deficiency, and four had a profound antibody deficiency comparable to common variable immunodeficiency (CVID). Three of the patients with profound antibody deficiency showed signs of reduced T-cell function measured as a low response to mitogen and/or antigen stimulation. The four patients with profound antibody deficiency suffered from more severe infections than the rest of the patient group. Three of them also had a history of both immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AHA). Our results suggest that a subgroup of individuals with 22q11.2DS can develop a severe antibody deficiency associated with lower respiratory tract infections and autoimmune conditions. Early diagnosis of hypogammaglobulinemia among these individuals is important in order to provide optimal treatment. We therefore recommend an immunological evaluation and follow-up among adults with 22q11.2DS who have a history of autoimmune conditions or recurrent infections.

Immunoglobulin G subclass levels and antibody responses to the 2009 influenza A (H1N1) monovalent vaccine among human immunodeficiency virus (HIV)-infected and HIV-uninfected adults

Immunoglobulin (Ig)G levels are important for antibody vaccine responses and IgG subclass deficiencies have been associated with severe 2009 influenza A (H1N1) infections. Studies have demonstrated variations in immune responses to the H1N1 vaccine, but the aetiology of this is unknown. We determined the associations between pre-vaccination overall and influenza-specific IgG subclass levels and 2009 H1N1-specific antibody responses post-vaccination (robust versus poor at day 28) stratified by human immunodeficiency virus (HIV) status. Logistic regression models were utilized to evaluate whether pre-vaccination IgG subclass levels were associated with the antibody response generated post-vaccination. We evaluated 48 participants as part of a clinical study who were stratified by robust versus poor post-vaccination immune responses. Participants had a median age of 35 years; 92% were male and 44% were Caucasian. HIV-infected adults had a median CD4 count of 669 cells/mm(3) , and 79% were receiving highly active anti-retroviral therapy. HIV-infected participants were more likely to have IgG2 deficiency (<240 mg/dl) than HIV-uninfected individuals (62% versus 4%, P < 0·001). No association of pre-vaccination IgG subclass levels (total or influenza-specific) and the antibody response generated by HIN1 vaccination in either group was found. In summary, pre-vaccination IgG subclass levels did not correlate with the ability to develop robust antibody responses to the 2009 influenza A (H1N1) monovalent vaccine. IgG2 deficiencies were common among HIV-infected individuals but did not correlate with poor influenza vaccine responses. Further investigations into the aetiology of disparate vaccine responses are needed.

A Scoring System to Determine the Need for Immunoglobulin Therapy in Patients with Humoral Immune Defects

Patients with varying degrees of immune deficiency often present for evaluation of the necessity of immunoglobulin therapy (Ig). While Ig is the standard of care in Common Variable Immune Deficiency (CVID), a scoring system may be useful in the decision to treat patients with milder humoral immune defects such as IgG deficiency.

IgG3 deficiency extends lifespan and attenuates progression of glomerulonephritis in MRL/lpr mice

BackgroundAntibodies of the IgG3 subclass have been implicated in the pathogenesis of the spontaneous glomerulonephritis observed in mice of the MRL/MpJ-Tnfrsf6lpr (MRL/lpr) inbred strain which have been widely studied as a model of systemic lupus erythematosus We have produced IgG3-deficient (-/-) mice with the MRL/lpr genetic background to determine whether IgG3 antibodies are necessary for or at least contributory to MRL/lpr-associated nephritis.ResultsThe gamma3 genotype (+/+ vs. +/- vs. -/-) did not appear to significantly affect serum titers of IgG auto-antibodies specific for double-stranded DNA (dsDNA) or α-actinin. However, while substantial serum titers of IgG3 auto-antibodies specific for double-stranded DNA (dsDNA) or α-actinin were seen in gamma3 +/+ mice, somewhat lower serum titers of these IgG3 auto-antibodies were found in gamma3 +/- mice, and gamma3 -/- mice exhibited baseline concentrations of these auto-antibodies. Analysis of immunoglobulins eluted from snap-frozen kidneys obtained from mice of all three gamma3 genotypes at ~18 weeks of age revealed much higher quantities of IgG in the kidneys from gamma3 +/+ than gamma3 -/- mice, and most IgG eluted from +/+ mice was IgG3. The serum creatinine levels in gamma3 +/+ mice substantially exceeded those of age-matched gamma3 -/- mice after ~21 weeks of age. Histopathological examination of kidneys from mice sacrificed at pre-determined ages also revealed more extensive glomerulosclerosis in gamma3 +/+ or +/- mice than in -/- mice beginning at 21 weeks of age. Survival analysis for IgG3-deficient and IgG3-producing MRL/lpr mice revealed that gamma3 -/- mice lived significantly longer (p = 0.0006) than either gamma3 +/- or +/+ mice. Spontaneous death appeared to be due to irreversible renal failure, because > 85% of glomeruli in kidneys from mice that died spontaneously were obliterated by glomerulosclerosis.ConclusionsThe available evidence suggests that IgG3 deficiency partially protects MRL/lpr mice against glomerulonephritis-associated morbidity and mortality by slowing or arresting the progression to glomerulosclerosis.ReviewersThis article was reviewed by Pushpa Pandiyan, Irun Cohen, and Etienne Joly.

Development of common variable immunodeficiency in IgA- and IgG2-deficient patients with systemic lupus erythematosus

BackgroundThere have been few reports on children who developed common variable immunodeficiency (CVID) in association with immunoglobulin A (IgA) and IgG2 deficiencies and systemic lupus erythematosus (SLE).Case-Diagnosis/TreatmentOur patient experienced nephrotic syndrome and acute respiratory distress syndrome (ARDS) caused by influenza A/H1N1 virus infection at 5 years of age. A diagnosis of IgA and IgG2 deficiency and SLE was made on the basis of severe proteinuria, hematuria, hypocomplementemia, high anti-DNA antibody and antinuclear antibody (ANA) titers, and malar rash. However, these clinical signs and symptoms and laboratory features disappeared after the administration of methylprednisolone pulse therapy and prednisolone. For the 5 years following the initial treatment for SLE, the patient experienced a number of infections and had a low serum total IgG level; she was eventually diagnosed with CVID. The administration of intravenous immunoglobulin (IVIG) was required to prevent subsequent infections, and no relapse of SLE was observed.ConclusionWe report the development of CVID in an IgA- and IgG2-deficient patient with SLE on the basis of multiple episodes of infection. To prevent the development of CVID in IgA- and IgG2-deficient patients with SLE, it is important to prevent immune dysregulation by the avoidance of infections through the use of IVIG therapy.

Clostridium difficile Small Bowel Enteritis in a Patient with IgG Deficiency

Purpose:Clostridium difficile (C. difficile) infection has been infrequently reported as a cause of diarrhea in the ileostomy patient, often with high morbidity and mortality due to delayed diagnosis. We present a case of C. difficile small bowel enteritis in an immunosuppressed patient successfully treated after early diagnosis and aggressive medical management. Case: A 44-yearold female patient with a history of immotile cilia syndrome, asthma, chronic bronchiectasis, and IgG deficiency was admitted with increased ostomy output. Three months prior, she had a subtotal colectomy with diverting loop ileostomy secondary to a sigmoid colon obstruction. In addition, she had multiple admissions for pulmonary issues and was treated with glucocorticoid tapers and antibiotics. At the time of admission, she was on prednisone 25 mg daily and had received a dose of IVIG one month prior for a low IgG level. On exam, she was afebrile with normal vital signs and an unremarkable physical exam. Pertinent labs included a WBC of 6.4 K/ul with a normal differential. Stool from her ostomy was found to be positive for C. difficile. During previous hospitalizations, her stools were negative for C. difficile. She was started on oral vancomycin and IV metronidazole and was discharged home on oral metronidazole. After missing 3 doses, she was readmitted for increased ostomy output and volume depletion. She was treated with IV metronidazole and oral vancomycin. She received a total of 23 days of antibiotics and did well after discharge. Her loop ileostomy was taken down five months later and the patient has done well. Discussion: C. difficile is a toxin-producing, anaerobic, gram-positive rod previously thought to be pathogenic only in the colon. Animal models have demonstrated that its toxins can generate a severe inflammatory response in small bowel mucosa. A recent review identified a total of 56 cases of C. difficile small bowel enteritis in the literature by 2010, with 48 reported after 2001. The vast majority were associated with colectomy or other bowel surgery. Additional pre-disposing factors included inflammatory bowel disease, immunosuppression, and antibiotic exposure. The mortality rate was 32% for the previously described cases, but our patient had a benign clinical course, likely due to early diagnosis and aggressive treatment. Since C. difficile small bowel enteritis is rare, there are no established guidelines on treatment. In our patient, we opted for dual therapy due to previously reported poor outcomes. Clinicians should consider C. difficile enteritis in any patient with increased ostomy output, especially those with prior antibiotic exposure or immunosuppression.

Cutaneous PAN and Common Variable Immunodeficiency: what causes what?

Background Cutaneous polyarteritis nodosa (c-PAN) is a necrotizing vasculitis of small and medium-sized vessels limited to the skin, characterized by the presence of subcutaneous nodular, painful, non purpuric lesions with or without livedo reticularis occurring predominantly in the lower extremities, with no systemic involvement. The cause of c-PAN is unknown: infectious agents in childhood and immunodeficiency in adults have been associated with the disease. Aim To our knowledge the association of c-PAN and Common Variable Immunodeficiency (CVID) has not been reported so far. Case report A 2 year-5 months old girl was referred for intermittent fever and cutaneous erythematous, painful nodular lesions on feet, ankles and pretibial regions. A skin biopsy showed a necrotizing non-granulomatous vasculitis. Diagnosis of cutaneous polyarteritis nodosa was made and treatment with methotrexate (MTX), prednisone and ibuprofen was started. One year later, due to insufficient response, MTX was switched to azathioprine. We obtained a good clinical control in 4 months, thus NSAIDs and steroids were progressively stopped. At an 8 months follow-up, laboratory test were all in the normal range, except for progressive hypogammaglobulinemia (IgA and IgM, 29.4 mg/dl; and 28 mg/dl; IgG= 571 mg/dl). Immunological tests showed: IgG2 deficiency (42 mg/dl) total white count at lower limits, with lymphopenia (21.6%); lymphocyte subpopulations showed deficiency of CD19+ B cells (3%, normal values: 6-25%) and a poor response to protein vaccines. Due to the 1-year persistent remission on therapy, AZA was tapered and stopped. After several months, hypogammaglobulinemia persisted, thus excluding a potential side effect related to AZA treatment. Six months later, due to a disease flare, AZA was restarted in addition to prednisone (1 mg/kg/die) and IVIG every 4 weeks (2 gr/ kg). IVIG treatment was added in order to combine their anti-inflammatory effect with the CVID replacement therapy. At last follow-up her c-PAN is in clinical remission on AZA only. IVIG treatment is still needed for replacement (400 mg/kg monthly), due to her CVID. Of note, during her long term (6 years) follow-up in our Unit, she never developed any major infection. Conclusions c-PAN and CVID are both due to immune system dysregulation, with not well known mechanisms. In our patient, immunosuppressive therapy could have induced a B-immunodeficiency, or could have uncovered a preexisting immunodeficient status. However, a casual association or the possibility of c-PAN as onset of CVID cannot be excluded.

Rothmund-Thomson syndrome: Immuno-osseous challenges

Results All patients had characteristic poikiloderma as well as thumb anomalies. They were born dysmaturely and presented with failure to thrive. Age at genetic diagnosis was 5y, 4y and 3y for P1, P2, P3. Osteopenia and abnormal metaphyseal trabeculation of bones were striking on the initial skeletal survey in all patients. Z-scores on DXA scan were -0.1, -1.1 and -1.2 for P1, P2, P3 respectively at presentation. The presentation in P2 was dramatic with 6 fractures in upper and lower extremities and subluxation of both radii. All patients were suffering from recurrent chest infections. P1 had granulomatous skin inflammation following primo VZV infection. All patients have low switched memory B cells for age, P1 has IgG2 deficiency. P1 and P3 have IgM deficiency. P1 and P3 have specific polysaccharide antibody deficiency. Results are pending for P2. All receive prophylactic antibiotics. P1 is treated with subcutaneous immunoglobulin substitution.

Renal tubular acidosis, food allergy, IgA and IgG deficiency in Mexican children

Results Median age 20 months (±12 months), 15 female (50%) 15 male(50%). IgA2 deficiency 16 (53%), IgG4 and IgA2 deficiencies 13 (43%), IgG4 deficiency 27 (90%), 29 patients had distal renal tubular acidosis (96%) 1 patient with proximal renal tubular acidosis. About food allergies, cow’s milk 28(93%), egg 18 (60%), wheat 0, corn 8 (26.6%), soy 2 (6.6%), non IgE mediated to cow’s milk 6 (20%), egg 6 (20%), soy 7 (23%), wheat 4 (13%), corn 1 (3.3%). The formula used to cow’s milk allergy was aminoacid based formula 19 (63.3%), extensively hydrolized formula 11 (36.6%). Gastroesophageal reflux was associated in 83.3%, wheezing 75%, diarrhea 33.3%, atopic dermatitis 25%, rhinitis 83.3%, urticaria 19.4%, constipacion 2.8%, blood stools 2.8%.

Serum killing of Ureaplasma parvum shows serovar-determined susceptibility for normal individuals and common variable immuno-deficiency patients

BackgroundMany Gram-negative bacteria, unlike Gram-positive, are directly lysed by complement. Ureaplasma can cause septic arthritis and meningitis in immunocompromised individuals and induce premature birth. Ureaplasma has no cell wall, cannot be Gram-stain classified and its serum susceptibility is unknown. MethodsSurvival of Ureaplasma serovars (SV) 1, 3, 6 and 14 (collectively Ureaplasma parvum) were measured following incubation with normal or immunoglobulin-deficient patient serum (relative to heat-inactivated controls). Blocking monoclonal anti-C1q antibody and depletion of calcium, immunoglobulins, or lectins were used to determine the complement pathway responsible for killing. ResultsEighty-three percent of normal sera killed SV1, 67% killed SV6 and 25% killed SV14; greater killing correlating to strong immunoblot identification of anti-Ureaplasma antibodies; killing was abrogated following ProteinA removal of IgG1. All normal sera killed SV3 in a C1q-dependent fashion, irrespective of immunoblot identification of anti-Ureaplasma antibodies; SV3 killing was unaffected by total IgG removal by ProteinG, where complement activity was retained. Only one of four common variable immunodeficient (CVID) patient sera failed to kill SV3, despite profound IgM and IgG deficiency for all; however, killing of SV3 and SV1 was restored with therapeutic intravenous immunoglobulin therapy. ConclusionsOnly the classical complement pathway mediated Ureaplasma-cidal activity, sometimes in the absence of observable immunoblot reactive bands.

Necrotizing myositis and septic shock caused by Haemophilus influenzae type f in a previously healthy man diagnosed with an IgG3 and a mannose-binding lectin deficiency

An increased incidence of infections by Haemophilus influenzae type f (Hif) has recently been suggested, but such infections have mainly been regarded as opportunistic. We present here a dramatic case of Hif necrotizing myositis and septic shock. A subsequently diagnosed IgG3 and mannose-binding lectin deficiency possibly contributed to the severe outcome.

Efficient Immunoglobulin Gene Disruption and Targeted Replacement in Rabbit Using Zinc Finger Nucleases

Rabbits are widely used in biomedical research, yet techniques for their precise genetic modification are lacking. We demonstrate that zinc finger nucleases (ZFNs) introduced into fertilized oocytes can inactivate a chosen gene by mutagenesis and also mediate precise homologous recombination with a DNA gene-targeting vector to achieve the first gene knockout and targeted sequence replacement in rabbits. Two ZFN pairs were designed that target the rabbit immunoglobulin M (IgM) locus within exons 1 and 2. ZFN mRNAs were microinjected into pronuclear stage fertilized oocytes. Founder animals carrying distinct mutated IgM alleles were identified and bred to produce offspring. Functional knockout of the immunoglobulin heavy chain locus was confirmed by serum IgM and IgG deficiency and lack of IgM+ and IgG+ B lymphocytes. We then tested whether ZFN expression would enable efficient targeted sequence replacement in rabbit oocytes. ZFN mRNA was co-injected with a linear DNA vector designed to replace exon 1 of the IgM locus with ∼1.9 kb of novel sequence. Double strand break induced targeted replacement occurred in up to 17% of embryos and in 18% of fetuses analyzed. Two major goals have been achieved. First, inactivation of the endogenous IgM locus, which is an essential step for the production of therapeutic human polyclonal antibodies in the rabbit. Second, establishing efficient targeted gene manipulation and homologous recombination in a refractory animal species. ZFN mediated genetic engineering in the rabbit and other mammals opens new avenues of experimentation in immunology and many other research fields.

IgG deficiency and expansion of CTG repeats in myotonic dystrophy

ObjectivesExpansion of CTG repeats in myotonic dystrophy (DM1) alters the regulated expression of numerous genes. It is considered to explain the major clinical features of DM1. IgG deficiency is common in DM1 and is due to altered FcRn-related hypercatabolism. We hypothesized that the IgG catabolic rate is correlated with CTG repeat expansion. MethodsCorrelations between serum immunoglobulin levels, peripheral lymphocyte subset counts and CTG repeat numbers were performed in 52 DM1 patients. ResultsSerum IgG and IgG1 levels were below the normal limit respectively in 54% and 72% of patients. Increasing CTG repeat numbers were significantly correlated with decreasing serum IgG and IgG1 levels, and with decreasing CD3+ T-cell and CD3+–CD8+ cell counts. An abnormal immunoglobulin profile at protein electrophoresis was found in 4 patients. ConclusionWe conclude that the catabolic rate of IgG is linked to expanded CTG repeats, possibly involving an altered immune response.

Pharmacokinetic Factors in IgG Supplementation by the Intravenous and Subcutaneous Routes

RATIONALE: The pharmacokinetic characteristics of IgG homeostasis and supplementation are not well described in humans. Serum IgG is routinely measured to diagnose and guide therapy for IgG deficiencies, but may not be truly representative of patients' clinical IgG status as a dosing tool.

Study of primary immunodeficiencies in Algeria

Primary immunodeficiencies (PIDs) are heritable disorders of immune system function. These defects are rare, but seem to be more frequent in populations with high consanguinity. The defect may affect T cells, B cells, phagocyte cells or complement proteins. Patients have increased susceptibility to recurrent infections, and may suffer from, allergy, auto-immune disorders or cancers. The assessment of 303 patients suspected to have a primary immunodeficiency during seven years (January 2003 to July 2010) allowed us to diagnose 75 PIDs aged between 3 months and 32 years: 51 (68%) males and 24 (32%) females; the sex ratio is 2.12. 40 % of the patients are the offspring of consanguineous marriages. The immunological tests that we used include measurment of serum IgG, IgA, IgM, IgE levels and IgG subclass levels; tetrazolium nitroblue test; lymphocyte immunophenotyping and flow cytometry evaluation of surface proteins as: CD11, CD15, CD18, MHC class II, CD40, CD40 ligand, CD25. We report in this study the results from the 75 patients: 13 have “severe combined immunodeficiency (SCID), 11: MHC II deficiency, 30: agammaglobulinaemia, 1: Hyper-IgM syndrome, 9: common variable immunodeficiency, 1: IgG2 deficiency, 9: phagocyte defects, and 1 ataxia-telangiectasia. The molecular characterization of these deficiencies is important for diagnosis in some cases, for prenatal diagnosis and for potential therapeutic intervention strategies. We plan to set up other tests for evaluation of the other PIDs.

Community Acquired MRSA Skin and Soft Tissue Infection and its Possible Relationship With IgG Deficiency and CD4 Lymphopenia

Staphylococcus aureus is the most common pathogen associated with infections of skin and soft tissue structures Staphylococcus aureus colonizes the skin of approximately 35% of Americans of which approximately 1% is methicillin resistant Staphylococcus aureus (MRSA). The vast majority of skin and soft tissue infections have been associated with Community acquired-MRSA strains, but other presentations such as pneumonia, necrotizing fascitis and on rare occasions, septicemia have occurred 4,5 . Risk factors for CA-MRSA infections include being a child, an athlete, a member of the armed forces or an intravenous drug user with the majority of these being immunocompetent 6,7 . CA-MRSA infections have also been reported in patients with immunodeficiency states such as HIV, cancer etc . This study was performed to identify any existing correlations between CA-MRSA skin infections and immunocompromised conditions, as assessed by IgG deficiency and CD4 lymphopenia and to define the local epidemiology of (CA-MRSA) skin infections in El Paso, Texas in an Infectious Disease Clinic over a 3 year period. MATERIAL AND METHODS Data was collected prospectively from the medical and laboratory records of outpatients seen at a Infectious Disease Clinic in El Paso, Texas between 2006 -2009. Inclusion criteria for analysis included: (1) Documented skin and soft tissue infections (SSTIs) , (2) Positive wound cultures obtained just prior to or at the time of evaluation, (3) No known previous history of MRSA colonization or infections, and (4) No recent history of hospitalization, nursing home admission, dialysis, surgery, indwelling catheter or devices that pass through the skin in the past year. Data collected included age, gender, complete blood count (CBC), IgG level and CD4 count. Possible confounders including diabetes, steroid use, cancer or other immunecompromised states and sick contacts were assessed. Description of the lesions included site and characteristics of the infection, as well as the clinical course including surgical intervention, antibiotic therapy and relapses or recurrences. If family members were susupected of having the same presentation, phone interviews or face to face contact was established to determine if they had a reasonable probability of having MRSA skin infections. Any cultures that were done on them by other physicians were reviewed. Patients were followed for an average of 2 years following their initial presentation. The definition of a cure was no further skin and soft tissue infections at the end of the 2 year period.

The Lower Serum Immunoglobulin G2 Level in Severe Cases than in Mild Cases of Pandemic H1N1 2009 Influenza Is Associated with Cytokine Dysregulation

The majority of patients with pandemic influenza H1N1 2009 had mild illness, but some, including those with no risk factors for severe disease, may succumb to this infection. Besides viral factors such as the D222/225G substitution of the hemagglutinin, host factors such as IgG2 subclass deficiency recently was reported to be associated with severe disease in a cohort of Australian patients besides other known risk factors, including underlying chronic illness, extremes of age, and pregnancy. We conducted a case-control study of 38 Asian patients with respiratory failure due to severe pandemic influenza and compared the results to those for 36 mild cases. None had selective IgG2 deficiency, but the level of IgG2 subclass was significantly lower in the severe cases (3.55 g/liter versus 4.75 g/liter; P = 0.002), whereas the levels of IgG1, IgG3, and IgG4 were not significantly different from those of the mild cases. Previous studies suggested that some IgHG2 and FcγRIIa genotypes were associated with IgG2 deficiency. The allelic frequency of the IgHG2 genotypes in our severe cases was not correlated with their levels of IgG2, while that of FcγRIIa was not significantly different from that of the general Han Chinese population (P = 0.216). Only the overall cytokine/chemokine profile (P = 0.029) and serum globulin level (P = 0.005) were found to be independently associated with the IgG2 level by multivariate analysis. The lower IgG2 level in our severe group might be related to cytokine dysregulation rather than being a significant risk factor for severe pandemic influenza. The importance of this finding for therapeutic intervention will require further studies of larger cohorts of patients.

Neuromyelitis optica-IgG(+) optic neuritis associated with celiac disease and dysgammaglobulinemia: A role for tacrolimus?

We present a pediatric case of recurrent optic neuritis, celiac disease, partial IgA and IgG3 deficiency in the context of anti-aquaporin-4 auto-immunity and familial IgA deficiency with celiac disease. Treatment with tacrolimus was successful in preventing disease relapses. This case stresses the relevance of central nervous system anti-aquaporin-4 auto-immunity in a broader context of immune dysregulation and neuro-immunology.

PA10 ABDOMINAL VASCULAR MALFORMATIONS AND PSEUDOHYPOPARATHYROIDISM TYPE 1A IN AN ADOLESCENT PATIENT. CASE REPORT

were EMA positive (not tested for TGA). Taken together, 13 of the 181 T1D children studied had CD, giving a prevalence of 7.18% (IC 95%: 3.8-12.3). Among the 117 siblings of T1D children studied, one with IgA deficiency and high titer of AGA IgG was found to be affected by celiac disease before screening. A total of 116 siblings were tested for EMA and 6 of these (5.17%) were positive. We performed TGA test only in 107 siblings and 6 (5.60%) were positive. Of these, 5 were also positive for EMA and 1 was EMA negative. All the 7 siblings with positive antibodies underwent jejunal biopsy; celiac disease was found in 5 subjects. Of these, 3 were EMA and TGA positive, 1 was EMA negative and TGA positive and 1 was EMA positive (not tested for TGA); 2 subjects both EMA and TGA positive, had a negative biopsy for celiac disease. Taken together 6 of 117 siblings of T1D children studied had celiac disease, giving a prevalence of 5.13% (IC 95%: 1.9-11.2). Conclusions: We found the prevalence of CD significantly higher in T1D children and their siblings than in the Italian general population (1%; IC 95% 0,6-1,3), investigated in the same period. These findings agree with figures reported from the latest population-based studies performed and should be correlated to common genetic background of T1D children and their siblings. As the prevalence of CD in siblings of T1D children is higher than the general population, the screening for CD should be extended to all first-degree relatives of patients with T1D.