Dendritic cells (DC) are professional antigen-presenting cells that play a key role in linking the innate and adaptive arms of the immune system. In vitro, DC perform critical functions such as antigen uptake and processing, priming of naïve T cells and production of cytokines to regulate other immune cells. In vivo experimental systems support a central role for DC in inducing protective immune responses but the effect of DC deficiency in existing whole animal models is smaller than would be predicted. Studies of human primary immunodeficiency disorders (PID) have significantly advanced our understanding of the development and function of other immune cells and provide some important information about DC. Although only a small number of rare monogenic PID that cause DC deficiency have been described to date, impaired DC function forms part of the immunophenotype of several PID and is likely to contribute to clinical presentation. This review focuses on what is known so far about the role of DC in PID and what implications this has for basic DC biology.

Introduction: Heterozygous mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with selective deficiencies to mycobacterial or fungal infections. Recent reports revealed that patients found to carry de novo heterozygous mutations in STAT1 encoding specific amino acid substitutions can go on to develop progressive combined immunodeficiency, distinct from the limited susceptibilities to infection previously reported for heterozygous STAT1 mutations. Objectives: We present a case of a mother and her son with chronic mucocutaneous candidiasis and T-cell dysfunction, both of whom lived longer than projected life expectancy with a heterozygous STAT1 mutation. The son lived to the age of 20 years and the mother to the age of 32 years. Methods: The son's blood sequencing of STAT1 was performed on a pure T-cell lineage at The Hospital for Sick Children and the Canadian Center for Primary Immunodeficiency, Toronto, Ontario. Results: STAT1 analysis revealed a heterozygous DNA binding domain mutation at Thr385Met. The patient proceeded to develop fulminant progressive multifocal leukoencephalopathy that ultimately led to his death. The patient's mother, although never confirmed to have STAT1 mutation with formal blood sequencing, had multiple comorbidities including progressive lymphopenia, hypogammaglobulinemia, recurrent Pseudomonas pneumonias with associated bronchiectasis, end-stage kidney disease requiring hemodialysis, and ultimately death due to multiple end organ failure associated sepsis. Conclusion: This is the first autosomal dominant transmission of the STAT1 DNA binding domain Thr385Met mutation with an extended lifespan. Statement of Novelty: Previous patients found to have heterozygous mutations of STAT1 that were associated with progressive combined immunodeficiency, arose de novo in each case. Presumed autosomal dominant transmission of a heterozygous STAT1 DNA binding domain Thr385Met mutation has not been reported.

Introduction: Mutations in the signal transducer and activator of transcription1 (STAT1) have been associated with a variety of clinical patterns. Interestingly patients with heterozygous mutations in the DNA binding domain (DBD) of STAT1 suffer acute and chronic colitis. Methods: To further analyze the role of STAT1 deficiency in intestinal inflammation, we employed protein expression analysis of total and activated STAT1 in intestinal biopsy samples from 2 patients with heterozygous mutations in the DBD of the STAT1 gene. Results: Both patients showed clinical and histological features of colitis. Total and activated STAT1 were decreased in duodenal and colonic enterocytes, and total STAT1 was found to be mislocalized in aggregates subapically. In addition, intestinal biopsy samples showed decreased numbers of lymphocytes. Patient-derived lymphoblasts demonstrated lack of viability and high susceptibility for cell death. Conclusion: STAT1 expression and distribution in the gut of patients with mutations in the DBD are abnormal, suggesting a primary role of STAT1 dysfunction in enterocytes in addition to the secondary effect of aberrant inflammation. Statement of novelty: Colitis associated with STAT1 mutations appears to have unique features distinct from typical inflammatory bowel disease.

Chronic granulomatous disease (CGD) is an inherited defect of leukocyte phagocytic function leading to recurrent infections. Autoimmune manifestations are reported in up to 6% of patients with CGD. We report a case of CGD presenting with arthritis as the first manifestation of disease. A 12-year-old Pakistani male of consanguineous parents presented with migratory arthritis and painless oral ulcerations of 6 months duration that were minimally responsive to nonsteroidal anti-inflammatory treatment. Initial assessment demonstrated elevated inflammatory markers (ESR 62), weakly positive ANA (titer 1:40), negative anti-DsDNA, and negative RF. He presented to the emergency department with fevers and arthritis. Repeat work-up suggested early Macrophage Activation Syndrome: normocytic anemia (Hgb 95 g/L), thrombocytopenia (Plt 141 × 10⁹/L), elevated LDH 1603, ferritin 1230 mcg/L, ESR 127, CRP 9.3, hypertiglycerdemia (3.2 mmoL/L) and mild transaminitis (ALT 63, AST 87), normal bone marrow (no hemophagocytosis), but mildly elevated Soluble CD 136 (1086 ng/mL) and Soluble IL-2 receptor (CD25) (1698 U/mL). He was treated with oral prednisone with symptom resolution. The arthritis relapsed after 1 month and the patient developed fever, productive cough, and pleuritic chest pain. Chest imaging revealed multiple nodular opacities and enlarged mediastinal lymph nodes. Aspergillus fumigatus complex was isolated from induced sputum prompting screening for primary immunodeficiency. Neutrophil oxidative burst function, as assessed by a dihydrorhodamine flow cytometry based assay, was low at 1.26 and 1.48 (normal range 32–300). Genetic analysis showed a previously described mutation in the NCF1 gene confirming the diagnosis of autosomal-recessive CGD. CGD can present with an exclusively rheumatologic presentation including arthritis and oral ulceration. Statement of Novelty: This case demonstrates that CGD can present with rheumatological symptoms prior to any infectious features.

Hematopoietic stem cell transplantation using HLA-mismatched related donors for the treatment of severe combined immunodeficiency has led to disappointing outcomes at our institution. This created an impetus to consider other donor sources when an HLA-matched related donor was not available. In 1988, a new protocol using HLA-matched unrelated donors was developed at our institution and continues to be used to date. This has contributed to improved outcomes and change in practice for patients with severe combined immunodeficiency. Statement of novelty: This report describes in detail the protocol for hematopoietic stem cell transplantations using HLA-matched unrelated donors for patients with severe combined immunodeficiency at our institution. This protocol is published for those centres wishing for guidance in setting up procedures for hematopoietic stem cell transplantation.