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J Allergy Clin Immunol. 2023 Oct 4:S0091-6749(23)01248-4. doi: 10.1016/j.jaci.2023.09.036. Online ahead of print.

ABSTRACT

BACKGROUND: Racial and ethnic disparities in life expectancy in the U.S. have been widely documented. To date, there remains a paucity of similar data in patients with inborn errors of immunity (IEI).

OBJECTIVE: To examine racial and ethnic differences in IEI mortality in the U.S.

METHODS: We analyzed the National Center for Health Statistics national mortality data from 2013 to 2018. We quantified age-adjusted death rate (ADR) and age-specific death rate (ASDR) from IEI for each major racial and ethnic group in the U.S, and examined the association of race and ethnicity with death at a younger age. For detailed Methods, please see the Methods section in this article’s Online Repository at www.jacionline.org.

RESULTS: During 2003 to 2018, IEI was reported as the underlying or contributing cause of death in 14,970 individuals nationwide. ADR was highest among Black patients (4.25 per 1,000,000 person-years), compared with 2.01, 1.71, 1.50, and 0.92 per 1,000,000 person-years for White, American Indian/Alaska Native (AIAN), Hispanic, and Asian/Pacific Islander (API) patients, respectively. Odds of death before age 65 years was greatest among Black patients (OR 5.15; 95% CI 4.61-5.76), followed by AIAN patients (OR 3.58; 95% CI 2.30-5.82), compared with White patients. Odds of death before age 24 years was greatest among Hispanic patients, compared with non-Hispanic patients (OR 3.60; 95% CI 3.08-4.18).

CONCLUSION: Our study highlights racial and ethnic disparities in IEI mortality and the urgent need to further identify and systematically remove barriers in care for historically marginalized patients with IEI.

PMID:37802474 | DOI:10.1016/j.jaci.2023.09.036

Medicine (Baltimore). 2023 Oct 6;102(40):e35246. doi: 10.1097/MD.0000000000035246.

ABSTRACT

Immune classification of ovarian cancer (OV) becomes more and more influential for its immunotherapy. However, current studies had few immune subtypes of OV. It is urgent to explore the immune subtypes and deeper hub immune-related genes (IRGs) of OV for follow-up treatment. A total number of 379 OV samples were obtained from UCSC online website. Single sample gene set enrichment analysis of 29 immune gene sets was used for identifying immune subtypes of OV and gene set variation analysis were used for exploring the hallmarks and Kyoto Encyclopedia of Genes and Genomes pathways of immune types. Two immunity subtypes (Immunity_H and Immunity_L) were identified by single sample gene set enrichment analysis. The OV patients in Immunity_H group had longer overall survival compared with those in Immunity_L group. The Immunity_H had higher stromal score, immune score and estimate score and the tumor purity had the adverse tendency. Besides, the gene set variation analysis enrichment results showed positive relationship between improved immunoreaction and pathways correlated to classical signaling pathway (PI3K/AKT/MTOR, P53, TNFA/NFkB signaling pathways) and immune responses (T/B cell receptor signaling pathways and primary immunodeficiency). Furthermore, 4 hub IRGs (CCR5, IL10RA, ITGAL and PTPRC) were jointly dug by weighted gene co-expression network construction and Cytoscape. Our team also explored the mutations of 4 hub IRGs and PTPRC showed nearly 7% amplification. Besides, 8 immune-checkpoint genes had higher expression in Immuity_H group compared with Immuity_L group, except CD276. The correlation between PD-1/PD-L1 and 4 hub IRGs were explored and gene set enrichment analysis were conducted to explore the underlying mechanisms of PTPRC in OV. Finally, western-blotting showed PTPRC could regulate immune checkpoint PD-L1 expression via JAK-STAT signaling pathway. In a word, 2 immune subtypes and 4 hub IRGs of OV were identified by multiple analysis.

PMID:37800814 | DOI:10.1097/MD.0000000000035246

Skin Health Dis. 2023 Aug 7;3(5):e273. doi: 10.1002/ski2.273. eCollection 2023 Oct.

ABSTRACT

Sinus histiocytosis or Rosai-Dorfman disease (RDD) is a rare disorder with severe lymphadenopathy and a limited clinical course, the aetiology of which is still controversial. The disease usually affects cervical nodes, with fever, polyclonal gammopathy, and leucocytosis with neutrophilia. Pure cutaneous involvement occurs as the only manifestation in only 3% of cases. Cutaneous RDD is often associated with infections, immunodeficiency, and autoimmune disorders. A 52-year-old patient presented with disseminated, recurrent, and relapsed pure cutaneous RDD that responded well to treatment with sirolimus and local infiltrations of methylprednisolone. The patient had multiple nonpainful nodular and tumour-like lesions, histiocytic infiltrates with emperipolesis were observed on histologic examination, and positive immunohistochemistry for CD68, and S100. There is no standardised treatment, then the patient was treated with various therapies, including systemic steroids, chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone), radiotherapy, and other immunosuppressive treatments. Some lesions were treated surgically, resulting in recurrence. Sirolimus and local infiltration with methylprednisolone were tried as salvage treatments, the patient responded well, reducing the incidence of new lesions during follow-up, and the size of the preexisting lesions.

PMID:37799357 | PMC:PMC10549808 | DOI:10.1002/ski2.273

J Food Sci. 2023 Oct 6. doi: 10.1111/1750-3841.16778. Online ahead of print.

ABSTRACT

Alcoholism is a serious public health problem, and the abuse of drinking seriously damages the health of people. Chitosan oligosaccharides (COSs) are small-molecule oligosaccharides with amino groups that have many unique properties. The neuroprotective effect of COS on alcohol-induced hippocampal injury in Sprague-Dawley (SD) rats was investigated. The discrimination ratio of the COS group in the Y-maze experiment was 59.3% higher than that of the ETOH group. Meanwhile, the discrimination index was less than 0 in the ETOH group but greater than 0 in the COS group during the object recognition test. The cells in the COS group were more tightly arranged than those in the ETOH group. Proteomics was used to identify differentially expressed proteins in the hippocampus. There were 27 differentially expressed proteins in the COS and ETOH group for further bioinformatic analysis. There are three enriched pathway categories, namely, primary immunodeficiency, hedgehog signaling, and sulfur relay system. Next, sonic hedgehog signaling pathway-related proteins were verified through western blotting. The protein expression level of β-arrestin-2 in the COS group was 2.85 times higher than that in the ETOH group. This work may contribute to understanding the underlying mechanism of the neuroprotective effect of COS against alcohol-induced hippocampal injury in SD rats.

PMID:37799098 | DOI:10.1111/1750-3841.16778

J Allergy Clin Immunol. 2023 Oct 3:S0091-6749(23)01244-7. doi: 10.1016/j.jaci.2023.09.032. Online ahead of print.

ABSTRACT

BACKGROUND: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency; PASLI) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation.

OBJECTIVE: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12-weeks; here we report results from an interim analysis of an ongoing open-label, single-arm extension study.

METHODS: Patients with APDS aged ≥12 years who completed NCT02435173 or had prior exposure to PI3Kδ inhibitors were eligible. The primary endpoint is safety, assessed via investigator-reported adverse events and clinical/laboratory evaluations. Secondary and exploratory endpoints include health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation.

RESULTS: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled – consisting of 26, 9 and 2 patients who previously received leniolisib, placebo or other PI3Kδ inhibitors, respectively. At the data cut-off (13 Dec 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE; most AEs were grades 1-3, none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (p=0.004) and reductions in immunoglobulin replacement therapy occurred in 10/27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias and normalized lymphocyte subsets.

CONCLUSION: Leniolisib was well-tolerated and maintained durable outcomes with up to 5-years exposure in 37 patients with APDS.

PMID:37797893 | DOI:10.1016/j.jaci.2023.09.032

Front Immunol. 2023 Sep 19;14:1264482. doi: 10.3389/fimmu.2023.1264482. eCollection 2023.

ABSTRACT

Common variable immunodeficiency (CVID) associated liver disease is an underrecognized and poorly studied non-infectious complication that lacks an established treatment. We describe a CVID patient with severe multiorgan complications, including non-cirrhotic portal hypertension secondary to nodular regenerative hyperplasia leading to diuretic-refractory ascites. Remarkably, treatment with rituximab, administered for concomitant immune thrombocytopenia, resulted in the complete and sustained resolution of portal hypertension and ascites. Our case, complemented with a literature review, suggests a beneficial effect of rituximab that warrants further research.

PMID:37795099 | PMC:PMC10546204 | DOI:10.3389/fimmu.2023.1264482

J Clin Immunol. 2023 Oct 5. doi: 10.1007/s10875-023-01579-4. Online ahead of print.

ABSTRACT

PURPOSE: Protein kinase C δ (PKCδ) deficiency is a rare genetic disorder identified as a monogenic cause of systemic lupus erythematosus in 2013. Since the first cases were described, the phenotype has expanded to include children presenting with autoimmune lymphoproliferative syndrome-related syndromes and infection susceptibility similar to chronic granulomatous disease or combined immunodeficiency. We review the current published data regarding the pathophysiology, clinical presentation, investigation and management of PKCδ deficiency.

METHODS: Literature review was performed using MEDLINE.

RESULTS: Twenty cases have been described in the literature with significant heterogeneity.

CONCLUSION: The variation in clinical presentation delineates the broad and critical role of PKCδ in immune tolerance and effector functions against pathogens.

PMID:37794137 | DOI:10.1007/s10875-023-01579-4

J Allergy Clin Immunol. 2023 Oct 2:S0091-6749(23)01208-3. doi: 10.1016/j.jaci.2023.09.027. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: To investigate outcomes of hematopoietic cell transplantation (HCT) for severe combined immunodeficiency (SCID), the Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children in the United States and Canada in a retrospective, multi-center natural history study.

METHODS: We evaluated the chronic and late effects (CLE) after HCT for SCID in 399 patients transplanted from 1982-2012 at 32 PIDTC centers. Eligibility criteria included survival to at least 2 years post-HCT without need for subsequent cellular therapy. CLE were defined as either conditions present at any time before 2 years from HCT that remained unresolved (chronic), or new conditions that developed beyond 2 years after HCT (late).

RESULTS: The cumulative incidence of CLE was 25% in those alive at 2 years, increasing to 41% at 15 years after HCT. CLE were most prevalent in the neurologic (9%), neurodevelopmental (8%) and dental (8%) categories. Chemotherapy-based conditioning was associated with decreased height z-score at 2-5 years post-HCT (p<0.001), and endocrine (p<0.001) and dental (p=0.05) CLE. CD4 count ≤500/μl and/or continued need for immunoglobulin replacement >2 years post-transplant were associated with lower height z-scores. Continued survival from 2 to 15 years post-HCT was 90%. The presence of any CLE was associated with increased risk of late death (HR 7.21; 2.71-19.18, p<0.001).

CONCLUSION: Late morbidity post-HCT for SCID was substantial, with an adverse impact on overall survival. This study provides evidence for development of survivorship guidelines based on disease characteristics and treatment exposures for patients after HCT for SCID.

PMID:37793572 | DOI:10.1016/j.jaci.2023.09.027

J Allergy Clin Immunol. 2023 Oct 2:S0091-6749(23)01209-5. doi: 10.1016/j.jaci.2023.09.028. Online ahead of print.

ABSTRACT

BACKGROUND: The autoimmune lymphoproliferative syndrome (ALPS) is a non-infectious and non-malignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline mono-allelic FAS (TNFRSF6) haplo-insufficient mutations associated with somatic events, such as loss of heterozygosity (LOH) on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double negative T cells (DN T), the pathognomonic T cell subset in ALPS, in which the somatic events accumulated.

OBJECTIVE: In four unrelated ALPS patients carrying a germline mono-allelic mutation of FADD (FAS associated death domain protein) inherited from a healthy parent, we sought to identify whether a somatic event affecting the FADD gene could be related to the disease onset.

METHODS: We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4⁺ or DN T cells.

RESULTS: We found homozygous FADD mutations in the DN T cells from all 4 patients which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity (LOH) was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline bi-allelic FADD mutations.

CONCLUSION: The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS.

CLINICAL IMPLICATIONS: Two out of four patients received sirolimus and were in remission. ALPS-FADD/sLOH patients can thus benefit from this targeted treatment which is standard of care in ALPS-FAS patients.

PMID:37793571 | DOI:10.1016/j.jaci.2023.09.028

Cureus. 2023 Aug 31;15(8):e44445. doi: 10.7759/cureus.44445. eCollection 2023 Aug.

ABSTRACT

Griscelli syndrome type 2 (GS2) is a rare, autosomal recessive condition caused by a mutation of the RAB27A gene that causes primary immunodeficiency and pigmentary dilution of skin and hair. It is a rare occurrence, with only 160 cases reported all over the world. It commonly progresses to hemophagocytic lymphohistiocytosis (HLH) due to immunodeficiency. We herein represent the case of a seven-month-old male child, the firstborn of a third-degree consanguineous marriage, who presented with recurrent viral infections and silvery grey hair. A definitive diagnosis of GS 2 was made in accordance with the pathognomonic appearance of hair on microscopic examination and whole genome sequencing, which revealed a homozygous missense mutation in exon 3 of the RAB27A gene. This article is being reported to highlight the rare incidence of this disease, its overlapping clinical features with malnutrition, the challenges faced in diagnosis, and the treatment modalities for it.

PMID:37791210 | PMC:PMC10544088 | DOI:10.7759/cureus.44445