Genomic Testing Identifies Monogenic Causes in Patients with Very Early-Onset Inflammatory Bowel Disease: A Multi-center Survey in an Iranian Cohort.

Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multi-center study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in one patient, respectively. In 3 patients (18.7%) no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD.

Inflammatory Responses of Women with Polycystic Ovary Syndrome in Vitro Differ from Healthy Women.

Polycystic ovary syndrome is a low-grade inflammatory state with increased serum levels of TNF-α. The present study has compared the inflammatory responses to breast cancer cell lines in women with PCOS with healthy women. Peripheral blood mononuclear cells (PBMCs) isolated from 50 women with PCOS and 50 healthy controls were cultured in the trans-well co-culture system. These cells were stimulated with two distinct breast cancer cell lines. The proliferation of PBMCs, CD3+CD8+T cell percentages, and tumor necrosis factor-alpha (TNF-α) concentration were evaluated after 48 and 72 hours of incubation. TNF-α concentration and the proliferation rate of PBMCs after 48 hours of incubation significantly increased in the PCOS group. However, after 72 hours, TNF-α secretion significantly decreased in the PCOS group. The ability of PBMCs to produce TNF-α decreased gradually in women with PCOS. When the effects of low-grade inflammation and endocrine conditions on the cells decrease, the inability of PBMCs to create an inflammatory response will be altered.

The Radiological Manifestations of Phagocytic Primary Immunodeficiencies in Children.

Primary immunodeficiencies are a diverse group of rare genetic disorders, among which phagocytic dysfunction impairs neutrophil function in a wide range of inherited disorders. Due to the heterogeneity of the disorders a multidisciplinary approach is often required for early diagnosis and initiation of appropriate treatments. The aim of this study was to evaluate the imaging findings in children admitted with phagocytic primary immunodeficiencies. Thirty-five children who fulfilled the inclusion criteria for phagocytic dysfunction were enrolled in this study. The patients were under close observation and monitoring from January 2011 until data locking in December 2017. The diagnosis of phagocytic immunodeficiency was confirmed by the patient's clinical course, presentation features, and laboratory data.  Among the 35 patients studied, the most frequent condition was chronic granulomatous disease (CGD) (23 patients), followed by different types of neutropenia (8 patients) and Job's syndrome (4 patients). Mediastinal and hilar lymphadenopathies and consolidation were the most frequent presentations. There was a significant relationship between mediastinal/hilar lymphadenopathies and fungal infections. A meaningful relationship was also found between pulmonary nodules without halo signs in patients with concomitant tuberculosis and fungal infections. A significant correlation was found between CGD, pulmonary fibrotic changes, and mediastinal lymphadenopathies. The most frequent radiological manifestations in children included mediastinal and hilar consolidations. Physicians' awareness of the radiological and clinical manifestations of these inherited diseases may be helpful in the early diagnosis and timely initiation of specific prophylaxis measures to prevent infections and also to initiate hematopoietic stem cell transplantation as the curative management modality.

JAGN1 mutation with distinct clinical features; two case reports and literature review.

Jagunal homolog 1 (JAGN1) has been recognized as an essential protein in neutrophil function. The mutated JAGN1 is responsible for immunodeficiency related to innate and humoral defense mechanisms. This deficiency impairs neutrophil development and function, leading to recurrent infections and facial dysmorphism as phenotypic consequences of severe congenital neutropenia (SCN). We report two siblings having the reported JAGN1 mutation with different clinical manifestations. Recurrent abscess formation unresponsive to antibiotic therapy, a history of delayed umbilical separation, frequent bacterial or fungal infection, dysmorphic face, failure to thrive, and other coexisting organ abnormalities should prompt physicians to syndromic immunodeficiencies involving neutrophils. Genetic investigations to elucidate the responsible mutation is critical as clinical management varies. Once the diagnosis is confirmed, a multi-disciplinary team should perform further workups to investigate other coexisting malformations and neurodevelopmental evaluation.

Novel PGM3 mutation in two siblings with combined immunodeficiency and childhood bullous pemphigoid: a case report and review of the literature.

BACKGROUND: Bullous pemphigoid is the most common autoimmune subepidermal blistering disorder with a low incidence in childhood. Combined immunodeficiencies (CIDs) are a group of monogenic inborn errors of immunity (IEIs) characterized by T- and B-cell dysfunction leading to recurrent infections, lymphoproliferation, predisposition to malignancy, and autoimmunity. Here, we report two Afghan siblings with a diagnosis of CID and extremely rare manifestation of diffuse bullous pemphigoid skin lesions. CASE PRESENTATION: The older sibling (patient 1) was a 32-month-old male with facial dysmorphism, protracted diarrhea, failure to thrive, recurrent oral candidiasis, recurrent otitis media with tympanic membrane perforation, who had been previously diagnosed with CID. While he was under treatment with intravenous immunoglobulin (IVIg), he developed extensive blistering lesions, which were diagnosed as childhood bullous pemphigoid. Methylprednisolone and azathioprine were added to the regimen, which resulted in a remarkable improvement of the skin lesions and also the feeding condition. However,2 weeks later, he was re-admitted to the intensive care unit (ICU) and eventually died due to fulminant sepsis. Later, his 12-month-old sister (patient 2) with similar facial dysmorphism and a history of developmental delay, food allergy, recurrent oral candidiasis, and respiratory tract infections also developed blistering skin lesions. She was under treatment for occasional eczematous lesions, and had been receiving IVIg for 3 months due to low levels of immunoglobulins. Further immunologic workup showed an underlying CID and thus treatment with IVIg continued, gradually improving her clinical condition. The genetic study of both siblings revealed a novel homozygous mutation in exon 7 of the PGM3 gene, c.845 T > C (p.Val282Ala). CONCLUSIONS: Dermatologic disorders may be the presenting sign in patients with CID and mutated PGM3. This case report further extends the spectrum of skin manifestations that could be observed in PGM3 deficiency and emphasizes the importance of considering CIDs during the assessment of skin disorders, particularly if they are extensive, recurrent, refractory to treatment, and/or associated with other signs of IEIs.

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin.

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.

Recalcitrant Cutaneous Warts in a Family with Inherited ICOS Deficiency.

Recalcitrant warts, caused by human papillomaviruses (HPVs), can be a cutaneous manifestation of inborn error of immunity. This study investigated the clinical manifestations, immunodeficiency, single-gene susceptibility, and HPV repertoire in a consanguineous family with severe sinopulmonary infections and recalcitrant warts. Clinical and immunologic evaluations, including FACS and lymphocyte transformation test, provided evidence for immunodeficiency. Combined whole-exome sequencing and genome-wide homozygosity mapping were utilized to disclose candidate sequence variants. Whole-transcriptome sequencing was used to concomitantly investigate the HPV genotypes and the consequences of detected sequence variants in the host. The proband, a male aged 41 years, was found to be homozygous for the c.6delG, p.Lys2Asnfs∗17 variant in ICOS, encoding the inducible T-cell costimulator. This variant was located inside the 5 megabase of runs of homozygosity on 2q33.2. RNA sequencing confirmed the deleteriousness of the ICOS variant in three skin biopsies revealing significant downregulation of ICOS and its ligand, ICOSLG. Reads unaligned to the human genome were applied to 926 different viruses, and α-HPV57, ß-HPV107, ß-HPV14, and ß-HPV17 were detected. Collectively, we describe a previously unrecognized inborn error of T-cell immunity to HPVs, indicating that autosomal recessive ICOS deficiency can underlie recalcitrant warts, emphasizing the immunologic underpinnings of recalcitrant warts at the nexus of human and viral genomic variation.

The Prevalence of Selective and Partial Immunoglobulin A Deficiency in Patients with Autoimmune Polyendocrinopathy.

BACKGROUND: Autoimmune disorders are reported as presenting signs in patients with immunoglobulin A (IgA) deficiency. Herein, we aim to evaluate serum IgA among patients with autoimmune polyendocrinopathy. METHODS: Patients with two or more autoimmune endocrinopathies were selected and the serum IgA levels were measured. Patients with an isolated low serum IgA (<7 mg/dL) after exclusion of other causes of hypogammaglobulinemia were considered as selective IgA deficiency (SIgAD), while partial IgA deficiency (PIgAD) was defined as IgA levels below lower limits of IgA normal range for age but higher than 7 mg/dL. RESULTS: Fifty-three patients (19 [35.8%] male and 34 [64.2%] female) with autoimmune polyendocrinopathy enrolled in the study. Parental consanguinity and positive family history of autoimmunity were reported in 38.0% and 52.9% of patients, respectively. Overall, IgA deficiency was observed in 5 (9.4%) patients including PIgAD in 3 (5.7%) and SIgAD in 2 (3.8%) patients. Among IgA deficient patients, the first autoimmune disorder was developed at earlier ages (p = .002), and the prevalence of infection (p = .002), lymphoproliferation (p = .021), and overlap between insulin-dependent diabetes mellitus and autoimmune thyroiditis (p = .032) were significantly higher than patients with normal IgA. Also, the number of autoimmune comorbidities was closely correlated with the occurrence of IgA deficiency (p = .008). CONCLUSION: The prevalence of IgA deficiency in patients with autoimmune polyendocrinopathy is higher than that in the general population. In these patients, immunologic workup may lead to early diagnosis of inborn error of immunity, which can positively impact the evolution of complications and even management of the autoimmune disorders.

Pulmonary Radiological Manifestations of Humoral and Combined Immunodeficiencies in a Tertiary Pediatric Center.

Respiratory diseases are considered as significant causes of morbidity and mortality in primary immunodeficiencies. This study aimed to reveal the radiologic patterns of thoracic involvement in these disorders. A total of 58 patients, including 38 cases with combined cellular-humoral and 20 cases with humoral immunodeficiencies, were enrolled in this study. The "combined" group consisted of 12 cases with severe combined immunodeficiency (SCID) and 26 cases with combined immunodeficiency. The "humoral" group included seven patients with Hyper IgM syndrome (HIGMs), seven cases with common variable immunodeficiency (CVID), three patients with X-linked agammaglobulinemia, and three patients with other types of humoral primary immunodeficiencies (PIDs). The mean age of patients at the time of evaluation was 3.3±3.8 and 5.3±3.9 years in combined and humoral groups, respectively. The findings of chest X-rays and CT scans were interpreted and compared. There was a significant difference for alveolar opacification between combined and humoral immunodeficiencies (58% vs. 30%). The bronchopneumonia-like pattern was detected as a significant finding in patients with SCID (42%) and HIGMs (43%). Atrophy of the thymus was detected significantly often in cases of SCID (67%). Two patients with CVID and lipopolysaccharide-responsive and beige-like anchor protein deficiency showed parenchymal changes of granulomatous lymphocytic interstitial lung disease. No significant difference was detected for bronchiectasis, bronchitis/bronchiolitis patterns, pleural effusion, and thoracic lymphadenopathy. Distinct subtypes of primary immunodeficiency may provoke differing and comparable radiological patterns of thoracic involvement; which can clue the clinician and radiologist to the diagnosis of the disease.

The Prevalence of Atopic Manifestations in 313 Iranian Patients with Inborn Errors of Immunity.

INTRODUCTION: Inborn errors of immunity (IEIs) are rare inherited disorders with a broad spectrum of manifestations. Here, we aimed to delineate the atopy burden in a cohort of patients with IEIs. METHODS: 313 patients with IEIs were enrolled in the study within a 9-years period, and data were collected via a questionnaire. All statistical analyses were performed using SPSS software (v. 25.0, Chicago, IL, USA). The statistical significance level was set at p < 0.05. RESULTS: Overall, 51 out of 313 (16.3%) patients were identified to have atopic manifestations. Food allergy was detected in 34 (10.2%), atopic dermatitis in 21 (6.7%), as well as allergic asthma and allergic rhinitis each in 4 (1.3%) patients. The allergic disorders were reported as initial manifestations among 14 out of 35 (40.0%) atopic patients. Most of these 51 patients fell within the category of combined immunodeficiency (CID) (n = 38, 74.5%), followed by, severe CID (SCID) (n = 5, 9.8%), common variable immunodeficiency (n = 3, 5.9%), chronic granulomatous disease (n = 3, 5.9%), selective IgA deficiency (n = 1, 2.0%), and leukocyte adhesion defect (n = 1, 2.0%). No patient with Mendelian susceptibility to mycobacteria was found to have atopic manifestation. Atopic dermatitis (p = 0.001) and food allergy (p < 0.001) were both significantly higher in patients with CID than in other IEI groups. Among atopic patients with CID and SCID, food allergy and atopic dermatitis were the most prevalent comorbidities. DISCUSSION/CONCLUSION: Atopic diseases may contribute to the clinical picture of IEIs, particularly in patients with CID. Atopy in association with other warning signs of IEIs increases the possibility of an underlying IEI.

Rapid Desensitization for Hypersensitivity Reactions to Chemotherapeutic Drugs; A Case Series.

Usage of cancer chemotherapeutics drugs can be associated with adverse drug reactions. When IgE-mediated drug reactions are formed following administration of a chemotherapeutics drug that is a drug of choice, drug desensitization protocols can be helpful. HSR can be allergic or nonallergic, but the clinical manifestations are similar. RDD is effective when used appropriately, however it is often over utilized instead of performing a drug challenge. RDD is both an acceptable approach and a high-risk treatment modality in patients, in whom the offending agent is the first choice in chemotherapy. The safety of this modality has been acceptable in large studies. The side effects are often less frequent and less severe by repeating the protocol. We present 4 cases of successful desensitization in cancer patients, who have developed IgE- mediated reactions to their major chemotherapy drug.

Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort.

BACKGROUND: Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses. OBJECTIVE: We intended to report most common monogenic PADs and to investigate how patients with PAD who were primarily diagnosed as suffering from agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID) have different clinical and immunological findings. METHODS: Stepwise next-generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as suffering from agammaglobulinemia, HIgM syndrome, and CVID. RESULTS: Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 Bruton's tyrosine kinase [BTK] and 6 µ heavy chain deficiencies), HIgM syndrome (21 CD40 ligand and 7 activation-induced cytidine deaminase deficiencies), and CVID (17 lipopolysaccharides-responsive beige-like anchor deficiency and 12 atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes) were identified. Clinical disease severity was significantly higher in patients with µ heavy chain and CD40 ligand mutations compared with patients with BTK (P = .003) and activation-induced cytidine deaminase (P = .009) mutations. Paralysis following live polio vaccination was considerably higher in patients with µ heavy chain deficiency compared with BTK deficiency (P < .001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in most patients with Immunodeficiency, Centromeric instability, and Facial dysmorphism were respiratory complications (P = .008), whereas first presentations in patients with lipopolysaccharides-responsive beige-like anchor deficiency were nonrespiratory complications (P = .008). CONCLUSIONS: This study highlights similarities and differences in the clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.

Severe Combined Immunodeficiency: A Case Series and Review from a Tertiary Pediatric Hospital.

Severe combined immunodeficiency syndrome (SCID) is a life-threatening condition leading to early infant death as a result of severe infection, due to impaired cellular and humoral immune systems. Various forms of SCID are classified based on the presence or absence of T cells, B cells and natural killer cells. Patients usually present with recurrent infections and failure to thrive. Definitive treatment is hematopoietic stem cell transplantation. To achieve the best outcome, it should be performed prior to the development of severe infection. In This study, we described 10 patients (6 male and 4 female) with SCID who were admitted to Mofid Children Hospital, Tehran, Iran, from 2006 to 2013. We reviewed patients' clinical manifestation, laboratory data, family history and outcome. The mean age at the time of diagnosis was 131.8 days. One patient had non-consanguineous parents. Seven patients received BCG vaccine before the diagnosis of SCID, three of them showed disseminated BCG infection. One patient presented with invasive pulmonary aspergillosis. Flow cytometric analysis showed T⁻B⁺NK⁻ in three patients, T⁻B⁻NK⁺ in five patients, T⁻B⁻NK⁻ in one patient, and T⁻B⁺NK⁺ in one patient. This study highlights the importance of early diagnosis and patient referral before the occurrence of serious infection.

Langerin+ dermal dendritic cells are critical for CD8+ T cell activation and IgH γ-1 class switching in response to gene gun vaccines.

The C-type lectin langerin/CD207 was originally discovered as a specific marker for epidermal Langerhans cells (LC). Recently, additional and distinct subsets of langerin(+) dendritic cells (DC) have been identified in lymph nodes and peripheral tissues of mice. Although the role of LC for immune activation or modulation is now being discussed controversially, other langerin(+) DC appear crucial for protective immunity in a growing set of infection and vaccination models. In knock-in mice that express the human diphtheria toxin receptor under control of the langerin promoter, injection of diphtheria toxin ablates LC for several weeks whereas other langerin(+) DC subsets are replenished within just a few days. Thus, by careful timing of diphtheria toxin injections selective states of deficiency in either LC only or all langerin(+) cells can be established. Taking advantage of this system, we found that, unlike selective LC deficiency, ablation of all langerin(+) DC abrogated the activation of IFN-γ-producing and cytolytic CD8(+) T cells after gene gun vaccination. Moreover, we identified migratory langerin(+) dermal DC as the subset that directly activated CD8(+) T cells in lymph nodes. Langerin(+) DC were also critical for IgG1 but not IgG2a Ab induction, suggesting differential polarization of CD4(+) T helper cells by langerin(+) or langerin-negative DC, respectively. In contrast, protein vaccines administered with various adjuvants induced IgG1 independently of langerin(+) DC. Taken together, these findings reflect a highly specialized division of labor between different DC subsets both with respect to Ag encounter as well as downstream processes of immune activation.