Israel Medical Association Journal

Inborn errors of immunity (IEI) result from pathogenic germline variants. These disorders are clinically characterized by increased susceptibility to infections and immune dysregulation, often leading to reduced survival [1]. By linking specific monogenic defects to immune phenotypes, IEI serve as experiments of nature that provide powerful models for dissecting human immunology [2]. The International Union of Immunological Societies (IUIS) currently classifies IEI into 10 major categories with overlapping phenotypes [3]: combined T- and B-cell immunodeficiencies, combined immunodeficiencies with syndromic features, predominantly antibody deficiencies, diseases of immune dysregulation, congenital defects of phagocytes, defects in intrinsic and innate immunity, autoinflammatory diseases, complement deficiencies, bone marrow failure, and phenocopies of IEIs. The recent 2024 IUIS update was designed to serve clinicians and researchers and to inform the design of targeted sequencing panels that facilitate the genetic diagnosis of IEI. It lists 508 genes underlying 559 conditions [3]. Of note, molecular, cellular, and clinical investigations of IEI have transformed our understanding of disease pathogenesis and enabled effective targeted therapies.

The field of inborn errors of immunity (IEI), previously known as primary immune deficiencies, includes susceptibility to infections, autoimmunity, uncontrolled inflammation and malignancy is rapidly expanding. Novel scientific discoveries together with artificial intelligence and machine learning are transformed into advances in the diagnosis and treatment of affected patients. These changes require adjustments in the knowledge, skills and attitudes of health care providers, and particularly expert clinicians managing patients with IEI. In this perspective, we highlighted some of the educational needs that should be adapted to ensure that the next generation of physicians provide best care for those affected by IEI.

Agammaglobulinemia was the first primary immunodeficiency identified in humans. It is characterized by an absent or significantly reduced number of mature B cells, decreased serum immunoglobulins, and recurrent infections beginning in infancy. The entity was first described in 1952 by Colonel Ogden Bruton at the Walter Reed Army Hospital in the United States. Bruton reported on an 8-year-old boy who had experienced 19 episodes of pneumonia over 4 years and was found to have a complete absence of antibody-containing γ-globulins in his serum [1].

Over time, through improvement in the immune and genetic investigations, our understanding of agammaglobulinemia has expanded enabling earlier diagnosis and treatment resulting in a change of the disease course.

Inborn errors of immunity (IEI), formerly referred to as primary immunodeficiencies, is a growing spectrum of over 550 genetically defined disorders of the immune system. As our understanding of the mechanisms of these disorders grows, immune dysregulation syndromes, autoimmunity, malignancy, bone marrow failure with immunodeficiency, and phenocopies are recognized as part of the clinical spectrum of IEI. Early recognition and accurate classification are critical as many IEI conditions have specific therapeutic implications, including targeted immune modulation, immunoglobulin replacement therapy, hematopoietic stem cell transplantation, and gene therapy. In this review, we present recent changes in classification, updated laboratory workup strategies, and therapeutic advances.

Inborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders affecting immune function, associated with a broad clinical spectrum including recurrent infections and immune dysregulation consisting of poly-autoimmunity, multiple allergies, and malignancies. To date, more than 550 causative genes have been identified, with inheritance patterns that may be autosomal dominant, autosomal recessive, or X-linked. Pathogenic variants may result in loss-of-function, dominant-negative, or gain-of-function effects, leading to variable phenotypic presentations and, at times, incomplete penetrance. Despite advances in genomic technologies, a definitive molecular diagnosis is reached in only 30–35% of cases. Early and accurate genetic diagnosis is crucial for guiding targeted therapy and providing effective genetic counseling. This review presents an updated overview of IEI from the geneticist's perspective and offers a practical approach to the genetic evaluation and diagnosis of these conditions.

Neutrophils serve as a cornerstone of innate immunity. Beyond their classical antimicrobial repertoire, these cells are versatile and capable of shaping the adaptive immune response through direct interactions with dendritic cells and lymphocytes in addition to cytokine-mediated effects. Additional functional phenotypes have also been described with regard to cancer and chronic inflammation. The clinical importance of neutrophils in host defense is perhaps best illustrated by the spectrum of inborn neutrophil disorders, ranging from congenital neutropenia to defects of adhesion and phagocytosis. We present a patient with clinical and laboratory features of hemophagocytic lymphohistiocytosis with a bacterial infection. The patient was subsequently found to carry a homozygous variant in the NCF2 gene, establishing a diagnosis of autosomal recessive chronic granulomatous disease (CGD). This presentation, combining cytokine storm with ongoing infection-driven inflammation, exemplifies the multifaceted role of neutrophils in health and disease. In this review, we provide clinical and immunological insights into neutrophil disorders, illustrated through a case of CGD as a paradigm of primary neutrophil dysfunction.

Background: Syndromic inborn errors of immunity (IEIs) are a heterogeneous group of disorders characterized by immune dysfunction associated with congenital anomalies and multisystem involvement. Tricho-hepato-enteric syndrome (THES) is an ultra-rare autosomal recessive syndromic IEI caused by biallelic pathogenic variants in TTC37 or SKIV2L. Delayed recognition is common because of its broad clinical spectrum.

Objectives: To describe the clinical, immunologic, genetic, and histopathologic characteristics of two children with THES and to highlight a structured diagnostic approach for syndromic immunodeficiencies.

Methods: We retrospectively reviewed the clinical presentation, laboratory investigations, immune phenotyping, endoscopic and histopathologic findings, and molecular analyses of two unrelated children diagnosed with THES at a tertiary pediatric immunology center. Molecular confirmation was obtained by whole-exome sequencing.

Results: Both patients presented during early infancy with intractable diarrhea, severe failure to thrive, characteristic dysmorphic features, brittle woolly hair, and inflammatory enteropathy requiring prolonged nutritional support. Immunologic evaluation demonstrated immune dysregulation, including inverted CD4/CD8 ratios, abnormalities of humoral immunity, and impaired vaccine-specific antibody responses. Histopathology revealed chronic active colitis with crypt distortion, inflammatory infiltrates, and crypt abscesses, consistent with very-early-onset inflammatory bowel disease-like enteropathy. Whole-exome sequencing identified homozygous pathogenic variants in SKIV2L in one patient and TTC37 in the other, establishing the diagnosis. Management included nutritional support, immunoglobulin replacement, antimicrobial prophylaxis, and immunomodulatory therapy.

Conclusions: Recognition of syndromic phenotype combined with comprehensive immune evaluation and early genomic testing facilitates prompt diagnosis, multidisciplinary management, genetic counseling, and consideration of emerging targeted therapies.

Background: Common variable immunodeficiency (CVID) is the most common clinically significant primary immunodeficiency disorder, typically presenting with hypogammaglobulinemia and recurrent infections. Mechanistically, CVID is caused by abnormal B-cell maturation or function. These abnormalities lead to an impaired ability to generate a normal quantity or diversity of antibodies and an impaired response to neo-antigens. In addition to the resulted immunodeficiency, CVID can also involve immune dysregulation affecting different organ systems, with the lungs being one of the more commonly involved organs. Granulomatous lymphocytic interstitial lung disease (GLILD) is a challenging and well known CVID-related complication. It is associated with high morbidity and increased risk of mortality.

Objectives: To describe the clinical and immunological features of five CVID patients with radiologic and/or pathologic features consistent with granulomatous lymphocytic interstitial lung disease.

Methods: We conducted a review of clinical, laboratory, imaging, and pathology data, as well as B-cell and T-cell immunophenotyping of patient PBMCs, focusing on unique characteristics of CVID GLILD patients.

Results: CVID GLILD patients showed several clinical characteristics, including multiorgan involvement with cytopenias and lymphoproliferation but without significant gastrointestinal involvement. B-cell phenotyping showed abnormal B-cell maturation and development with severely impaired class switching. In addition, unique T-cell phenotype with low to near-absent naive CD4⁺ T cells was observed.

Conclusions: Lung involvement in the form of GLILD is associated with significant co-morbidity and typical B-cell and T-cell immunophenotyping. Patients should be actively screened for the possibility of GLILD, especially when regularly performed lymphocyte immunophenotyping suggests similar patterns.

Inborn errors of immunity (IEI), formerly known as primary immunodeficiencies (PID), comprise a diverse group of genetic disorders characterized by increased susceptibility to infections, autoimmunity, autoinflammatory conditions, allergies, and malignancies. These disorders exhibit a broad spectrum of clinical manifestations, including extra-hematopoietic manifestations, which may also present later in life. IEI diagnosis has significantly advanced, in line with the common use of next-generation sequencing-based genetic platforms, such as whole-exome and whole-genome sequencing. Treatment approaches have evolved beyond infection management to include curative therapies such as hematopoietic stem cell transplantation, gene therapy, and targeted pharmacologic treatments. In this review, we explore recent advancements in the understanding, diagnosis, and treatment of IEI, emphasizing the rapid progress in this expanding field.