Primary Human Immunodeficiency Research Articles

Intermediate uveitis in common variable immunodeficiency (CVID) associated with a heterozygous variant in the TNFRSF13B gene.

To report on a rare case of intermediate uveitis occurring in a patient with common variable immunodeficiency (CVID) and a heterozygous TNFRSF13B variant. Observational case report. A 23-year-old male presented with a 3-month history of increasing floaters and blurred vision to both eyes. He had been treated with topical and intravitreal corticosteroids by his local ophthalmologist nine months before. Ocular examination demonstrated bilateral intermediate uveitis with retinal vasculitis. He had been treated with intravenous immunoglobulins during childhood, due to primary humoral immunodeficiency. Systemic work-up for other causes of intermediate uveitis was unremarkable, notably no features of systemic sarcoid-like disease were detected. Initial treatment with mycophenolate mofetil showed insufficient response, and upon switching to adalimumab, clinical remission was achieved. Immunocytometry and genetic work-up revealed a smB+CD21norm subtype of CVID and a heterozygous TNFRSF13B variant. This report of CVID-associated intermediate uveitis in a patient with a heterozygous TNFRSF13B variant highlights the potential involvement of the eye within CVID-associated autoimmunity and the role for anti-TNF blockade in this challenging group of patients.

Studying the cellular basis of small bowel enteropathy using high-parameter flow cytometry in mouse models of primary antibody deficiency.

Primary immunodeficiencies are heritable defects in immune system function. Antibody deficiency is the most common form of primary immunodeficiency in humans, can be caused by abnormalities in both the development and activation of B cells, and may result from B-cell-intrinsic defects or defective responses by other cells relevant to humoral immunity. Inflammatory gastrointestinal complications are commonly observed in antibody-deficient patients, but the underlying immune mechanisms driving this are largely undefined. In this study, several mouse strains reflecting a spectrum of primary antibody deficiency (IgA-/-, Aicda-/-, CD19-/- and JH -/-) were used to generate a functional small-bowel-specific cellular atlas using a novel high-parameter flow cytometry approach that allows for the enumeration of 59 unique cell subsets. Using this cellular atlas, we generated a direct and quantifiable estimate of immune dysregulation. This estimate was then used to identify specific immune factors most predictive of the severity of inflammatory disease of the small bowel (small bowel enteropathy). Results from our experiments indicate that the severity of primary antibody deficiency positively correlates with the degree of immune dysregulation that can be expected to develop in an individual. In the SI of mice, immune dysregulation is primarily explained by defective homeostatic responses in T cell and invariant natural killer-like T (iNKT) cell subsets. These defects are strongly correlated with abnormalities in the balance between protein (MHCII-mediated) versus lipid (CD1d-mediated) antigen presentation by intestinal epithelial cells (IECs) and intestinal stem cells (ISCs), respectively. Multivariate statistical approaches can be used to obtain quantifiable estimates of immune dysregulation based on high-parameter flow cytometry readouts of immune function. Using one such estimate, we reveal a previously unrecognized tradeoff between iNKT cell activation and type 1 immunity that underlies disease in the small bowel. The balance between protein/lipid antigen presentation by ISCs may play a crucial role in regulating this balance and thereby suppressing inflammatory disease in the small bowel.

A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece.

Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6-14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.

Clinical and experimental treatment of primary humoral immunodeficiencies.

Selective IgA deficiency (sIgAD), common variable immunodeficiency (CVID), and transient hypogammaglobulinemia of infancy (THI) are the most frequent forms of primary antibody deficiencies. Difficulties in initial diagnosis, especially in the early childhood, the familiar occurrence of these diseases, as well as the possibility of progression to each other suggest common cellular and molecular patomechanism and a similar genetic background. In this review, we discuss both similarities and differences of these three humoral immunodeficiencies, focusing on current and novel therapeutic approaches. We summarize immunoglobulin substitution, antibiotic prophylaxis, treatment of autoimmune diseases, and other common complications, i.e. cytopenias, gastrointestinal complications, and granulomatous disease. We discuss novel therapeutic approaches such as allogenic stem cell transplantation and therapies targeting-specific proteins, dependent on the patient's genetic defect. The diversity of possible therapeutics models results from a great heterogeneity of the disease variants, implying the need of personalized medicine approach as a future of primary humoral immunodeficiencies treatment.

Flow-cytometry as an auxiliary in the diagnosis of primary humoral immunodeficiencies.

Antibody deficiencies encompass a wide spectrum of pathologies and constitute approximately 50 % of primary immunodeficiencies; with cytometry, it is possible to evaluate the immune status rapidly, effectively and at low cost. To assess, by means of flow cytometry, the cells of patients with three types of primary humoral immunodeficiencies. Using flow cytometry, blood samples from patients and healthy subjects were analyzed with different monoclonal antibodies. Using various stains, a severe decrease in B lymphocytes was shown in patients with X-linked agammaglobulinemia, as well as a lack of CD154 expression in patients with hyper-immunoglobulin M syndrome, and heterogeneity of B lymphocyte subpopulations in patients with common variable immunodeficiency. Flow cytometry enables early diagnosis of primary immunodeficiencies with a high level of confidence and, in many cases, identification of the genes involved.

Zebrafish: A Relevant Genetic Model for Human Primary Immunodeficiency (PID) Disorders?

Primary immunodeficiency (PID) disorders, also commonly referred to as inborn errors of immunity, are a heterogenous group of human genetic diseases characterized by defects in immune cell development and/or function. Since these disorders are generally uncommon and occur on a variable background profile of potential genetic and environmental modifiers, animal models are critical to provide mechanistic insights as well as to create platforms to underpin therapeutic development. This review aims to review the relevance of zebrafish as an alternative genetic model for PIDs. It provides an overview of the conservation of the zebrafish immune system and details specific examples of zebrafish models for a multitude of specific human PIDs across a range of distinct categories, including severe combined immunodeficiency (SCID), combined immunodeficiency (CID), multi-system immunodeficiency, autoinflammatory disorders, neutropenia and defects in leucocyte mobility and respiratory burst. It also describes some of the diverse applications of these models, particularly in the fields of microbiology, immunology, regenerative biology and oncology.

Assessing SARS-CoV-2 Antigen Specific T-cell Responses After mRNA Vaccination and/or Omicron Variant COVID-19 Infection in Patients with Primary Humoral Immunodeficiencies

SARS-CoV-2 infection has significantly contributed to morbidity and mortality in patients with primary humoral immunodeficiencies, such as those with X-linked agammaglobulinemia (XLA) and common variable immunodeficiency (CVID). Currently, there is insufficient data to determine if mRNA vaccination and/or previous COVID-19 infection confers protection against rapidly mutating SARS-CoV-2 variants in patients with primary humoral immunodeficiencies. Evaluation of T-cell specific immune responses following vaccination against SARS-CoV-2 and omicron variant specific COVID-19 infection may help elucidate underlying mechanisms of protection for patients with primary humoral immunodeficiencies.

Real-World Outcomes After Switching to Immune Globulin Subcutaneous 16.5% In Patients with Primary Humoral Immunodeficiency: A 3-Year Study

Immune globulin subcutaneous 16.5% solution (IGSC 16.5%) is used to treat primary humoral immunodeficiency (PI) in adults and pediatric patients aged 2 years and older. There is little data on the impact of switching IGSC therapies. We assessed outcomes in PI patients who switched from an alternative IGSC product to IGSC 16.5%.

Comparison of pulmonary lesions using lung ultrasound and high-resolution computed tomography in adult patients with primary humoral immunodeficiencies.

Pulmonary involvement is the most common complication in patients with predominantly antibody deficiencies (PADs). Therefore, patients require repeated imaging tests. Unlike high-resolution computed tomography (HRCT), lung ultrasonography (LUS) does not expose patients to X-rays or contrast agents, and can be performed even at the bedside. This study aimed to evaluate lung lesions using simultaneous LUS and HRCT in a group of patients with PADs. Twenty-nine adult patients (13 women and 16 men) diagnosed with PADs according to the ESID criteria (23 Common variable immunodeficiency, 2 X-linked agammaglobulinemia, 2 IgG subclass deficiencies, and 2 Unspecified hypogammaglobulinemia) were included in the study. The mean age was 39.0 ± 11.9 years. The mean time elapsed between the first symptoms of PADs and the examination was 15.4 ± 10.1 years. Lung ultrasonography and high-resolution computed tomography were performed simultaneously according to a defined protocol during the clinic visits. In both examinations, lesions were compared in the same 12 regions: for each lung in the upper, middle, and lower parts, separately, front and back. A total of 435 lesions were described on LUS, whereas 209 lesions were described on HRCT. The frequencies of lesions in the lung regions were similar between LUS and HRCT. In both examinations, lesions in the lower parts of the lungs were most often reported (LUS 60.9% vs. HRCT 55.5%) and least often in the upper parts of the lungs (LUS 12.7% vs. HRCT 12.0%). The most frequently described lesions were LUS consolidations (99; 22.8%) and HRCT fibrosis (74; 16.5%). A statistically significant relationship was found in the detection of fibrosis in 11 of the 12 regions (phi = 0.4-1.0). Maximum values of the phi coefficient for the upper part of the left lung were recorded. Compared with HRCT, LUS is an effective alternative for evaluating and monitoring pulmonary lesions in adult patients with PADs, especially for pulmonary fibrosis.

Immunogenicity and Safety of the Spikevax® (Moderna) mRNA SARS-CoV-2 Vaccine in Patients with Primary Humoral Immunodeficiency

Introduction: Reports on the immunogenicity and efficacy of the Spikevax® vaccine against SARS-CoV-2 in immunodeficient patients are still scarce. We aimed to evaluate the safety and immunogenicity of the vaccine in patients with primary humoral immunodeficiency. Methods: We enrolled 46 patients, including 34 patients with common variable immunodeficiency (CVID), 10 patients with unclassified hypogammaglobulinemia (HypoIg), and 2 patients with X-linked agammaglobulinemia. We collected the blood samples before vaccination (D 0), and 10 days (D +38) and 90 days (D +118) after the second vaccination. Further, we quantified SARS-CoV-2-specific T-cell response (QuantiFERON ELISA test), serum anti-RBD IgG, and anti-RBD IgA-specific antibodies (enzyme immunoassay). Results: We found that the vaccination elicited predominantly mild adverse events, comparable to healthy population. Vaccination response negatively correlated with a value of Immune Deficiency and Dysregulation Activity in all measured parameters. D +38, seroconversion for anti-RBD IgG and anti-RBD IgA was observed in 65% and 21% CVID patients, respectively. SARS-CoV-2-specific T-cell response was detected in less than 50% of CVID patients. Meanwhile, HypoIg patients had 100%, 90%, and 60% positivity rates for anti-RBD IgG, anti-RBD IgA, and T-cell response, respectively. Three months after the second vaccination, 82% of the responders remained positive for anti-RBD IgG, but only less than 50% remained positive for T-cell activity in CVIDs. Low immunogenicity was observed in patients with lung involvement and/or rituximab treatment history. No SARS-CoV-2 infection was reported within 6 months after the second vaccination. Conclusion: Spikevax® seems to be safe with satisfactory immunogenicity in patients with primary humoral immunodeficiency.

Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI.

Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary immunodeficiency in humans. The genetic cause of CVID is still unknown in about 70% of cases. Ten percent of CVID patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 13B gene (TNFRSF13B), encoding TACI. Mutations in TNFRSF13B alone may not be sufficient for the development of CVID, as 1% of the healthy population carry these mutations. The common hypothesis is that TACI mutations are not fully penetrant and additional factors contribute to the development of CVID. To determine these additional factors, we investigated the perturbations of transcription factor (TF) binding and the transcriptome profiles in unstimulated and CD40L/IL21-stimulated naïve B cells from CVID patients harboring the C104R mutation in TNFRSF13B and compared them to their healthy relatives with the same mutation. In addition, the proteome of stimulated naïve B cells was investigated. For functional validation, intracellular protein concentrations were measured by flow cytometry. Our analysis revealed 8% less accessible chromatin in unstimulated naïve B cells and 25% less accessible chromatin in class-switched memory B cells from affected and unaffected TACI mutation carriers compared to healthy donors. The most enriched TF binding motifs in TACI mutation carriers involved members from the ETS, IRF, and NF-κB TF families. Validation experiments supported dysregulation of the NF-κB and MAPK pathways. In steady state, naïve B cells had increased cell death pathways and reduced cell metabolism pathways, while after stimulation, enhanced immune responses and decreased cell survival were detected. Using a multi-omics approach, our findings provide valuable insights into the impaired biology of naïve B cells from TACI mutation carriers.

Normal Immunoglobulin (Human) 10% and Recombinant Human Hyaluronidase (HyQvia)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses immunoglobulin human and recombinant human hyaluronidase (HyQvia) as a solution for subcutaneous infusion, available in the following strengths:
 
 normal immunoglobulin (human) 10%: 2.5 g/25 mL, 5 g/50 mL, 10 g/100 mL, 20 g/200 mL, 30 g/300 mL
 recombinant human hyaluronidase: 200 units/1.25 mL, 400 units/2.5 mL, 800 units/5 mL, 1,600 units/10 mL and 2,400 units/15 mL
 
 
 Indication: As replacement therapy for primary humoral immunodeficiency and secondary humoral immunodeficiency in adult patients.

Physiologically-based pharmacokinetic modeling of immunoglobulin and antibody coadministration in patients with primary human immunodeficiency.

Intravenous immunoglobulin (IVIG) (2000 mg/kg) increased the clearance of the mouse monoclonal antibody 7E3, directed against platelet integrin IIb/IIIa (alpha IIb beta 3, CD41/CD61) in rodents. We wanted to investigate the effect of IVIG on clearance of monoclonal antibodies in humans as there is extremely limited data regarding this interaction in the literature. Using the tyrosine protein kinase KIT anti‐cluster of differentiation 117 (c‐Kit) humanized monoclonal antibody (JSP191) as a case study, we used physiologically‐based pharmacokinetic (PBPK) modeling to evaluate the pharmacokinetic interaction between monoclonal antibodies and IVIG at doses (300–600 mg/kg) administered to patients with primary human immunodeficiency (PI). We first characterized the interaction between monoclonal antibodies and IVIG in PK‐Sim®/MoBi® using published literature data, including the following: IVIG plus 7E3 in mice and rats and IVIG plus the human anti‐C5 monoclonal antibody tesidolumab in adults with end‐stage renal disease. We next developed a PBPK model using digitized data for JSPI91 alone in older adults with myelodysplastic syndrome and acute myeloid leukemia and in pediatric patients with severe combined immunodeficiency (SCID). Finally, we simulated the impact of IVIG (300–2000 mg/kg) coadministration with JSP191 on the area under the curve of JSP191 in patients with SCID. Model predictions were within 1.5‐fold of observed values for 7E3 plus IVIG and tesidolumab plus IVIG as well as for JSP191 administered alone. Based on our simulations, IVIG doses ≥500 mg exceeded the 80%–125% no‐effect boundaries. IVIG treatment with monoclonal antibodies in patients with PI may result in a clinically significant interaction depending on the IVIG dose administered and the exposure–response relationship for the specific monoclonal antibody.

Normal Immunoglobulin (Human) 10% and Recombinant Human Hyaluronidase (HyQvia)


 CADTH recommends that HyQvia should be reimbursed for the treatment of primary humoral immunodeficiency and secondary humoral immunodeficiency if certain conditions are met.
 HyQvia should only be covered to treat adults with primary or secondary humoral immunodeficiency if it is covered in a similar way as other immunoglobulin replacement therapies (IgRTs) currently reimbursed for the treatment of these conditions.
 HyQvia should only be reimbursed if prescribed by a specialist with appropriate knowledge and training in primary and secondary humoral immunodeficiency and if treatment with HyQvia does not cost more than the least costly IgRT currently reimbursed for this condition.

COVID-19 Infection in Patients with Humoral Immunodeficiency: A Case Series and Literature Review.

BackgroundThe coronavirus 2019 disease (COVID-19) has infected many individuals worldwide and continues to pose a significant threat to those with weakened immune systems. The data evaluating the clinical outcomes of patients with humoral immunodeficiencies that contract COVID-19 is limited and conflicting.ObjectiveTo describe the clinical outcomes of COVID-19 infections in patients with primary humoral immunodeficiency and compare results to current literature.MethodsWe conducted a retrospective cohort review on 15 patients with a humoral immunodeficiency defined as Common Variable Immunodeficiency, Specific Antibody Deficiency, or unspecified hypogammaglobulinemia, who contracted COVID-19. Severity scores were determined to evaluate the clinical outcomes of these patients.ResultsOf our 15-patient cohort, 33% of individuals with a humoral immunodeficiency infected with COVID-19 had moderate to severe disease, requiring hospitalization or resulting in death. COVID-19 mortality rate was found to be 7%. All 5 of our patients with severe COVID-19 infection had at least 1 comorbidity or risk factor.ConclusionWithin our cohort of humoral immunodeficient patients infected with COVID-19, we found a higher rate of moderate to severe COVID-19 infection and worse clinical outcomes, particularly in patients with comorbidities or risk factors.

Evaluation of MicroRNA-125b-5p and Transcription Factors BLIMP1 and IRF4 Expression in Unsolved Common Variable Immunodeficiency Patients.

Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary humoral immunodeficiencies characterized by failure in the final differentiation of B lymphocytes. The majority of CVID cases have no identified genetic defect, and epigenetic alteration could be involved in the pathogenesis of CVID. Hence, we aimed to evaluate the expression of hsa-miR-125b-5p -and, B lymphocyte-induced maturation protein-1(BLIMP-1) and interferon regulatory protein-4 (IRF-4) in a group of CVID patients with no definitive genetic diagnosis in comparison with healthy individuals. Ten CVID patients (all known genes excluded) and 10 age and sex-matched healthy controls participated in the study. B lymphocytes were isolated and expression of miR-125b-5p, IRF4, and BLIMP1 were evaluated by real-time polymerase chain reaction (RT-PCR). Moreover, B cell subsets were analyzed by flow cytometry. The results showed that the relative expression of miR-125b-5p in CVID patients was increased while it was decreased for the BLIMP1 and IRF4 transcription factors compared with the healthy controls. Although a reduction was observed in switched and non-switched memory B cells among all high-miR patients, these subsets were decreased in patients with normal miRexpression (71.0% and 85.0%, respectively). Our results suggest that overexpression of miR-125b-5p affects the terminal differentiation of B cells in a selected group of CVID patients by downregulating the BLIMP-1 gene and more intensively for the IRF-4 gene expressions.

There is no gene for CVID - novel monogenetic causes for primary antibody deficiency.

'There is no gene for fate' (citation from the movie 'GATTACA') - and there is no gene for CVID. Common Variable ImmunoDeficiency (CVID) is the most prevalent primary immunodeficiency in humans. CVID is characterized by an increased susceptibility to infections, hypogammaglobulinemia, reduced switched memory B cell numbers in peripheral blood and a defective response to vaccination, often complicated by autoimmune and autoinflammatory conditions. However, as soon as a genetic diagnosis has been made in a patient with CVID, the diagnosis must be changed to the respective genetic cause (www.esid.org). Therefore, there are genetic causes for primary antibody deficiencies, but not for CVID. Primary antibody deficiencies (PADs) are a heterogeneous group of disorders. Several attempts have been made to gain further insights into the pathogenesis of PAD, using unbiased approaches such as whole exome or genome sequencing. Today, in just about 35% of cases with PAD, monogenic mutations (including those in the gene TNFRSF13B) can be identified in a set of 68 genes [1•]. These mutations occur either sporadically or are inherited and do explain an often complex phenotype. In our review, we not only discuss gene defects identified in PAD patients previously diagnosed with CVID and/or CVID-like disorders such as IKZF1, CTNNBL1, TNFSF13 and BACH2, but also genetic defects which were initially described in non-CVID patients but have later also been observed in patients with PAD such as PLCG2, PIK3CG, PMS2, RNF31, KMT2D, STAT3. We also included interesting genetic defects in which the pathophysiology suggests a close relation to other known defects of the adaptive immune response, such as DEF6, SAMD9 and SAMD9L, and hence a CVID-like phenotype may be observed in the future. However, alternative mechanisms most likely add to the development of an antibody-deficient phenotype, such as polygenic origins, epigenetic changes, and/or environmental factors.

6.34 Comparison of Primary Humoral Immunodeficiencies in Autism Spectrum Disorder (ASD) and Other Pediatric-Onset Psychiatric Disorders

6.34 Comparison of Primary Humoral Immunodeficiencies in Autism Spectrum Disorder (ASD) and Other Pediatric-Onset Psychiatric Disorders

TACI Mutations in Primary Antibody Deficiencies: A Nationwide Study in Greece.

Background and objectives: Monoallelic (heterozygous) or biallelic (homozygous or compound heterozygous) TACI mutations have been reported as the most common genetic defects in patients with common variable immunodeficiency (CVID), which is the most common clinically significant primary immunodeficiency in humans. The aim of our study was to evaluate the prevalence and any correlations of TACI defects in Greek patients with primary antibody deficiencies. Materials and Methods: 117 patients (male/female: 53/64) with CVID (110) and a combined IgA and IgG subclass deficiency (7) with a CVID-like clinical phenotype were enrolled in the study. Genomic DNA was extracted from peripheral blood and the molecular analysis of the TACI gene was performed by PCR (Polymerase Chain Reaction) and sequencing of all 5 exons, including exon–intron boundaries. Results: Seventeen patients (14.5%) displayed TACI defects, four (23.5%) carried combined heterozygous mutations and 13 (76.5%) carried single heterozygous mutations. The most frequently detected mutation was C104R (58.8%), followed by I87N (23.5%) and A181E (11.8%), while R20C, C62Y, P151L, K188M and E236X mutations were present in only one patient each. Patients with TACI defects were more frequently male (p = 0.011) and displayed a benign lymphoproliferation (splenomegaly and lymph node enlargement, p = 0.047 and p = 0.002, respectively), had a history of tonsillectomy (p = 0.015) and adenoidectomy (p = 0.031) and more frequently exhibited autoimmune cytopenias (p = 0.046). Conclusions: Considering that accumulating evidence suggests several CVID patients have a complex rather than a monogenic inheritance, our data further support the notion that TACI mutations, particularly as monoallelic defects, should be primarily considered as susceptibility co-factors and/or modifiers of primary antibody deficiencies.

Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK.

Since Dr. Ogden Bruton’s 1952 paper describing the first human primary immunodeficiency disease, the peripheral membrane binding signaling protein, aptly named Bruton’s tyrosine kinase (BTK), has been the target of intense study. Dr. Bruton’s description of agammaglobulinemia set the stage for ultimately understanding key signaling steps emanating from the B cell receptor. BTK is a multidomain tyrosine kinase and in the decades since Dr. Bruton’s discovery it has become clear that genetic defects in the regulatory domains or the catalytic domain can lead to immunodeficiency. This finding underscores the intricate regulatory mechanisms within the BTK protein that maintain appropriate levels of signaling both in the resting B cell and during an immune challenge. In recent decades, BTK has become a target for clinical intervention in treating B cell malignancies. The survival reliance of B cell malignancies on B cell receptor signaling has allowed small molecules that target BTK to become essential tools in treating patients with hematological malignancies. The first-in-class Ibrutinib and more selective second-generation inhibitors all target the active site of the multidomain BTK protein. Therapeutic interventions targeting BTK have been successful but are plagued by resistance mutations that render drug treatment ineffective for some patients. This review will examine the molecular mechanisms that drive drug resistance, the long-range conformational effects of active site inhibitors on the BTK regulatory apparatus, and emerging opportunities to allosterically target the BTK kinase to improve therapeutic interventions using combination therapies.