Phase 3 randomized trial of mavorixafor, CXCR4 antagonist, in WHIM syndrome.

We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist for participants with Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤400/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. Primary endpoint was time (hours) above ANC threshold ≥500/µL (TATANC; over 24 hours). Secondary endpoints included TAT absolute lymphocyte count ≥1000/µL (TATALC; defined similar to TATANC); absolute changes in white blood cell (WBC), ANC, and ALC from baseline; annualized infection rate; infection duration and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n=14; placebo, n=17), mavorixafor least squares (LS) mean TATANC was 15.0 hours, placebo 2.8 hours (P<0.001). Mavorixafor LS mean TATALC was 15.8 hours, placebo 4.6 hours (P<0.001). Higher absolute WBC, ANC, and ALC levels were seen with mavorixafor than placebo at each timepoint assessed. Annualized infection rates were 60% lower with mavorixafor versus placebo (LS mean 1.7 versus 4.2; nominal P=0.007) and total infection scores were 40% lower (7.4 [95% CI, 1.6-13.2] versus 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor-treated participants showed significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration. Mavorixafor was well tolerated in participants with WHIM syndrome. Trial was registered at ClinicalTrials.gov NCT03995108.

Treatment with Elapegademase Restores Immunity in Infants with Adenosine Deaminase Deficient Severe Combined Immunodeficiency.

PURPOSE: Patients with adenosine deaminase 1 deficient severe combined immunodeficiency (ADA-SCID) are initially treated with enzyme replacement therapy (ERT) with polyethylene glycol-modified (PEGylated) ADA while awaiting definitive treatment with hematopoietic stem cell transplant (HSCT) or gene therapy. Beginning in 1990, ERT was performed with PEGylated bovine intestinal ADA (ADAGEN®). In 2019, a PEGylated recombinant bovine ADA (Revcovi®) replaced ADAGEN following studies in older patients previously treated with ADAGEN for many years. There are limited longitudinal data on ERT-naïve newborns treated with Revcovi. METHODS: We report our clinical experience with Revcovi as initial bridge therapy in three newly diagnosed infants with ADA-SCID, along with comprehensive biochemical and immunologic data. RESULTS: Revcovi was initiated at twice weekly dosing (0.2 mg/kg intramuscularly), and monitored by following plasma ADA activity and the concentration of total deoxyadenosine nucleotides (dAXP) in erythrocytes. All patients rapidly achieved a biochemically effective level of plasma ADA activity, and red cell dAXP were eliminated within 2-3 months. Two patients reconstituted B-cells and NK-cells within the first month of ERT, followed by naive T-cells one month later. The third patient reconstituted all lymphocyte subsets within the first month of ERT. One patient experienced declining lymphocyte counts with improvement following Revcovi dose escalation. Two patients developed early, self-resolving thrombocytosis, but no thromboembolic events occurred. CONCLUSION: Revcovi was safe and effective as initial therapy to restore immune function in these newly diagnosed infants with ADA-SCID, however, time course and degree of reconstitution varied. Revcovi dose may need to be optimized based on immune reconstitution, clinical status, and biochemical data.

Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, posttransplant, protein-losing) associated with SHG and highlights key areas for future investigation.

Mesenchymal stromal cells reprogram monocytes and macrophages with processing bodies.

Mesenchymal stromal cells (MSCs) are widely used in clinical trials because of their ability to modulate inflammation. The success of MSCs has been variable over 25 years, most likely due to an incomplete understanding of their mechanism. After MSCs are injected, they traffic to the lungs and other tissues where they are rapidly cleared. Despite being cleared, MSCs suppress the inflammatory response in the long term. Using human cord tissue-derived MSCs (hCT-MSCs), we demonstrated that hCT-MSCs directly interact and reprogram monocytes and macrophages. After engaging hCT-MSCs, monocytes and macrophages engulfed cytoplasmic components of live hCT-MSCs, then downregulated gene programs for antigen presentation and costimulation, and functionally suppressed the activation of helper T cells. We determined that low-density lipoprotein receptor-related proteins on monocytes and macrophages mediated the engulfment of hCT-MSCs. Since a large amount of cellular information can be packaged in cytoplasmic RNA processing bodies (p-bodies), we generated p-body deficient hCT-MSCs and confirmed that they failed to reprogram monocytes and macrophages in vitro and in vivo. hCT-MSCs suppressed an inflammatory response caused by a nasal lipopolysaccharide challenge. Although both control and p-body deficient hCT-MSCs were engulfed by infiltrating lung monocytes and macrophages, p-body deficient hCT-MSCs failed to suppress inflammation and downregulate MHC-II. Overall, we identified a novel mechanism by which hCT-MSCs indirectly suppressed a T-cell response by directly interacting and reprogramming monocytes and macrophages via p-bodies. The results of this study suggest a novel mechanism for how MSCs can reprogram the inflammatory response and have long-term effects to suppress inflammation.

The Role of T Helper Type 2 (Th2) Cytokines in the Pathogenesis of Eosinophilic Granulomatosis with Polyangiitis (eGPA): an Illustrative Case and Discussion.

PURPOSEOF REVIEW: The pathogenesis of eosinophilic granulomatosis with polyangiitis (eGPA) is driven largely by CD4 + type 2 helper T cells (Th2), B cells, and eosinophils. Interleukin (IL)-4 and IL-13 are critical cytokines in Th2 cell-mediated inflammation; however, inhibition of IL-4 and IL-13 does not reduce serum eosinophil counts and has even been associated with hypereosinophilia. This review explores the role of IL-4, IL-5, and IL-13 in Th2-mediated inflammation to consider the potential clinical consequences of inhibiting these individual cytokines in eGPA. RECENT FINDINGS: Treatments for eosinophilic granulomatosis with polyangiitis (eGPA) are rapidly evolving through using biologic therapies to modulate the Th2 inflammatory response via eosinophil inhibition. While IL-4, IL-5, IL-13, and IL-25 can all affect eosinophils, only IL-5 inhibition has demonstrated therapeutic benefit to-date. In this review, we report a clinical vignette of a patient with adult-onset asthma who developed severe manifestations of eGPA after switching from mepolizumab (an IL-5 inhibitor) to dupilumab (an inhibitor of IL-4 and IL-13). By understanding the role of IL-4, IL-5, and IL-13 in Th2-mediated vasculitis, we can start to understand how eGPA might respond differently to focused cytokine inhibition.

eConsults' Impact on Care Access and Wait Times in Rheumatology.

BACKGROUND/OBJECTIVE: A growing number of health systems have implemented eConsults to improve access to specialty advice, but few studies have described their use in rheumatology or impact on visit wait times. We evaluated the uptake of an eConsult program and its impact on wait times for in-person rheumatology visits. METHODS: In this quality improvement project, we analyzed electronic health record data from 4 intervention clinics and 4 comparison clinics, 12 months before and after implementation of an eConsult program. We compared median wait time for rheumatology appointments using a pre-post difference-in-differences analysis and quantile regression, adjusting for patient age, race, sex, clinic pair, and primary insurance payer. We also interviewed 11 primary care providers from the intervention clinics and conducted a rheumatology provider focus group (n = 4) to elucidate experiences with the program. RESULTS: Rheumatologists recommended management in primary care or referral to another specialty for 41% of eConsults, reducing initial demand for in-person visits. The median wait times dropped in the intervention and the comparison clinics (42 and 25 days, respectively). Intervention clinic median wait time dropped 17 days more than comparison clinics, and this was nonstatistically significant (p = 0.089). eConsults fit provider care tasks best for triage or initial workup for diagnosis, and less well when tests required interpretation, or when back and forth communication was needed to manage the patient's condition. CONCLUSIONS: Implementation of eConsults for rheumatology was associated with reduced wait times for rheumatology appointments and supported primary care providers in the triage and workup for a substantial portion of patients.

A Mimic of Ankylosing Spondylitis, Ochronosis: Case Report and Review of the Literature.

PURPOSE OF REVIEW: Ochronosis and alkaptonuria are manifestations of the same condition-a rare autosomal recessive disorder resulting from a constitutional lack of homogentisate 1,2-dioxygenase (HGD) with the consequent accumulation of homogentisic acid (HGA). In ochronosis, HGA undergoes autoxidation as well as enzymatic oxidation to form an ochronotic pigment that accumulates in cartilage and connective tissues. In the beginning, there is homogentisic aciduria and pigmentation of cartilages and other connective tissues. In later years, generalized osteoarthritis of the spine and large joints, termed ochronotic arthropathy, develops. RECENT FINDINGS: The diagnosis is confirmed by quantitative measurement of HGA in urine and mutation analysis of the HGD gene. One of the differential diagnoses for the skin findings is exogenous ochronosis, a limited hyperpigmentation of skin caused by some chemicals. As for the lumbar spine findings, there can be radiographic similarities with ankylosing spondylitis (AS) including reduced intervertebral disc spaces and loss of lumbar lordosis; however, ochronosis will spare the sacroiliac joint, and the lumbar spine will show dense, wafer-like disk calcification with a vacuum disc phenomenon and broad syndesmophytes. Here, we present a case of a patient with probable ochronosis that was treated many years as ankylosing spondylitis without response, and we provide a review of the current literature on ochronosis pathogenesis, diagnosis, and treatment.

Hydroxychloroquine and COVID-19: a Rheumatologist's Take on the Lessons Learned.

PURPOSE OF REVIEW: Told from the viewpoint of rheumatologists, this review tells the story of hydroxychloroquine and its swift ascent to become a household name as a therapeutic strategy against the novel SARS-CoV-2 virus. This review describes the history, mechanisms, pharmacokinetics, therapeutic applications, and safety profile of hydroxychloroquine as an immunomodulatory and antiviral agent. It also summarizes the major studies that launched and assessed the use of hydroxychloroquine against COVID-19 infection. RECENT FINDINGS: More recent literature calls into question the long-held dogma that endolysosomal alkalinization is the primary mode of action of hydroxychloroquine. Ongoing uncertainty about the multiple potential mechanisms contributing to the therapeutic effect of hydroxychloroquine in rheumatic and viral disease led to a natural avenue for exploration in the treatment of COVID-19. Taken as a whole, the literature does not support utilizing hydroxychloroquine to treat or prevent infection from the SARS-CoV-2 virus. This is, at least in part, due to the wide variability in hydroxychloroquine pharmacokinetics between patients and difficulty achieving adequate target tissue concentrations of hydroxychloroquine without encountering unacceptable toxicities. Hydroxychloroquine continues to be a routinely prescribed, well-tolerated, effective, and low-cost treatment for rheumatic disease. Its therapeutic versatility has led to frequent repurposing for other conditions, most recently as an investigative treatment against the SARS-CoV-2 virus. Despite overall negative findings, the intense study of hydroxychloroquine against COVID-19 infection has enhanced our overall understanding of how hydroxychloroquine operates in autoimmune disease and beyond.

Paget's Disease of Bone: Osteoimmunology and Osteoclast Pathology.

PURPOSE OF REVIEW: The purpose of this review is to recognize clinical features of Paget's disease of bone and to describe how the osteoclast, a myeloid-derived cell responsible for bone resorption, contributes to the disease. RECENT FINDINGS: Recent studies have identified several variants in SQSTM1, OPTN, and other genes that may predispose individuals to Paget's disease of bone; studies of these genes and their protein products have elucidated new roles for these proteins in bone physiology. Understanding the pathologic mechanisms in the Pagetic osteoclast may lead to the identification of future treatment targets for other inflammatory and autoimmune diseases characterized by abnormal bone erosion and/or osteoclast activation.

Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology.

Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.

On Command Drug Delivery via Cell-Conveyed Phototherapeutics.

Herein, the use of red blood cells (RBCs) as carriers of cytoplasmically interned phototherapeutic agents is described. Photolysis promotes drug release from the RBC carrier thereby providing the means to target specific diseased sites. This strategy is realized with a vitamin B12-taxane conjugate (B12-TAX), in which the drug is linked to the vitamin via a photolabile CoC bond. The conjugate is introduced into mouse RBCs (mRBCs) via a pore-forming/pore-resealing procedure and is cytoplasmically retained due to the membrane impermeability of B12. Photolysis separates the taxane from the B12 cytoplasmic anchor, enabling the drug to exit the RBC carrier. A covalently appended Cy5 antenna sensitizes the conjugate (Cy5-B12-TAX) to far red light, thereby circumventing the intense light absorbing properties of hemoglobin (350-600 nm). Microscopy and imaging flow cytometry reveal that Cy5-B12-TAX-loaded mRBCs act as drug carriers. Furthermore, intravital imaging of mice furnish a real time assessment of circulating phototherapeutic-loaded mRBCs as well as evidence of the targeted photorelease of the taxane upon photolysis. Histopathology confirms that drug release occurs in a well resolved spatiotemporal fashion. Finally, acoustic angiography is employed to assess the consequences of taxane release at the tumor site in Nu/Nu-tumor-bearing mice.

Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus.

Apoptotic debris, autoantibody, and IgG-immune complexes (ICs) have long been implicated in the inflammation associated with systemic lupus erythematosus (SLE); however, it remains unclear whether they initiate immune-mediated events that promote disease. In this study, we show that PBMCs from SLE patients experiencing active disease, and hematopoietic cells from lupus-prone MRL/lpr and NZM2410 mice accumulate markedly elevated levels of surface-bound nuclear self-antigens. On dendritic cells (DCs) and macrophages (MFs), the self-antigens are part of IgG-ICs that promote FcγRI-mediated signal transduction. Accumulation of IgG-ICs is evident on ex vivo myeloid cells from MRL/lpr mice by 10 wk of age and steadily increases prior to lupus nephritis. IgG and FcγRI play a critical role in disease pathology. Passive transfer of pathogenic IgG into IgG-deficient MRL/lpr mice promotes the accumulation of IgG-ICs prior to significant B cell expansion, BAFF secretion, and lupus nephritis. In contrast, diminishing the burden IgG-ICs in MRL/lpr mice through deficiency in FcγRI markedly improves these lupus pathologies. Taken together, our findings reveal a previously unappreciated role for the cell surface accumulation of IgG-ICs in human and murine lupus.

Single Cell Chemical Cytometry of Akt Activity in Rheumatoid Arthritis and Normal Fibroblast-like Synoviocytes in Response to Tumor Necrosis Factor α.

The etiology of rheumatoid arthritis (RA) is poorly understood, and 30% of patients are unresponsive to established treatments targeting tumor necrosis factor α (TNFα). Akt kinase is implicated in TNFα signaling and may act as a barometer of patient responses to biologic therapies. Fluorescent peptide sensors and chemical cytometry were employed to directly measure Akt activity as well as proteolytic activity in individual fibroblast-like synoviocytes (FLS) from RA and normal subjects. The specificity of the peptide reporter was evaluated and shown to be a valid measure of Akt activity in single cells. The effect of TNFα treatment on Akt activity was highly heterogeneous between normal and RA subjects, which was not observable in bulk analyses. In 2 RA subjects, a bimodal distribution of Akt activity was observed, primarily due to a subpopulation (21.7%: RA Subject 5; 23.8%: RA Subject 6) of cells in which >60% of the reporter was phosphorylated. These subjects also possessed statistically elevated proteolytic cleavage of the reporter relative to normal subjects, suggesting heterogeneity in Akt and protease activity that may play a role in the RA-affected joint. We expect that chemical cytometry studies pairing peptide reporters with capillary electrophoresis will provide valuable data regarding aberrant kinase activity from small samples of clinical interest.

Immune Gamma Globulin Therapeutic Indications in Immune Deficiency and Autoimmunity.

Immune gamma globulin (IgG) has a long history in the treatment of both primary immune deficiency and autoimmune disorders. Disease indications continue to expand and new-generation products increase the versatility of delivery. This review encompasses a historical perspective as well as current and future implications of human immune globulin for the treatment of immune-mediated illness.

Roles of chemokines CCL2 and CCL5 in the pharmacokinetics of PEGylated liposomal doxorubicin in vivo and in patients with recurrent epithelial ovarian cancer.

Nanoparticles (NPs) are cleared by monocytes and macrophages. Chemokines CCL2 and CCL5 are key mediators for recruitment of these immune cells into tumors and tissues. The purpose of this study was to investigate effects of CCL2 and CCL5 on the pharmacokinetics (PKs) of NPs. Mice deficient in CCL2 or CCL5 demonstrated altered clearance and tissue distribution of polyethylene glycol tagged liposomal doxorubicin (PLD) compared to control mice. The PK studies using mice bearing SKOV3 ovarian cancer xenografts revealed that the presence of tumor cells and higher expression of chemokines were significantly associated with greater clearance of PLD compared to non-tumor bearing mice. Plasma exposure of encapsulated liposomal doxorubicin positively correlated with the total exposure of plasma CCL2 and CCL5 in patients with recurrent epithelial ovarian cancer treated with PLD. These data emphasize that the interplay between PLD and chemokines may have an important role in optimizing PLD therapy. FROM THE CLINICAL EDITOR: The use of nanoparticles as drug delivery carriers is gaining widespread acceptance in the clinical setting. However, the underlying pharmacokinetics of these novel drugs has not really been elucidated. In this interesting article, the authors carried out experiments using mice deficient in CCL2 or CCL5 to study the clearance of liposomal system. They showed the important role the immune system played and would enable better designs of future drug delivery systems.

Targeting the molecular and cellular interactions of the bone marrow niche in immunologic disease.

Recent investigations have expanded our knowledge of the regulatory bone marrow (BM) niche, which is critical in maintaining and directing hematopoietic stem cell (HSC) self-renewal and differentiation. Osteoblasts, mesenchymal stem cells (MSCs), and CXCL12-abundant reticular (CAR) cells are niche components in close association with HSCs and have been more clearly defined in immune cell function and homeostasis. Importantly, cellular inhabitants of the BM niche signal through G protein-coupled surface receptors (GPCRs) for various appropriate immune functions. In this article, recent literature on BM niche inhabitants (HSCs, osteoblasts, MSCs, CAR cells) and their GPCR mechanistic interactions are reviewed for better understanding of the BM cells involved in immune development, immunologic disease, and current immune reconstitution therapies.

Autoimmune lymphoproliferative syndrome: an update and review of the literature.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by immune dysregulation due to a defect in lymphocyte apoptosis. The clinical manifestations may be noted in multiple family members and include lymphadenopathy, splenomegaly, increased risk of lymphoma, and autoimmune disease, which typically involves hematopoietic cell lines manifesting as multilineage cytopenias. Since the disease was first characterized in the early 1990s, there have been many advances in the diagnosis and management of this syndrome. The inherited genetic defect of many ALPS patients has involved (FAS) pathway signaling proteins, but there remain those patients who carry undefined genetic defects. Despite ALPS having historically been considered a primary immune defect presenting in early childhood, adult onset presentation is increasingly becoming recognized and more so in genetically undefined patients and those with somatic FAS mutations. Thus, future research may identify novel pathways and/or regulatory proteins important in lymphocyte activation and apoptosis.

CD40 ligand antagonist dazodalibep in Sjögren's disease: a randomized, double-blinded, placebo-controlled, phase 2 trial.

Sjögren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sjögren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 ± 0.6; PBO, -4.1 ± 0.6; P = 0.0167) and population 2 (DAZ, -1.8 ± 0.2; PBO, -0.5 ± 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164 .

A Novel Transmembrane CXCR4 Variant That Expands the WHIM Genotype-Phenotype Paradigm.

Warts, Hypogammglobulinemia, Infections, Myelokathexis (WHIM) syndrome is a rare immunodeficiency disease that results from impaired leukocyte trafficking (myelokathexis) predominately caused by gain-of-function variants in C-X-C chemokine receptor type 4 (CXCR4). Clinical manifestations of WHIM syndrome can differ in familial forms or in people harboring identical CXCR4 variants. All known pathogenic CXCR4 variants associated with WHIM syndrome (CXCR4WHIM) to date are localized in the intracellular C-terminus of CXCR4. We identified 4 unrelated patients with variable WHIM-like clinical presentations harboring a novel heterozygous CXCR4 variant (c.250G>C; p.D84H) localized at a highly conserved position in the transmembrane domain of the receptor outside the C-terminus. Functional characterization of the CXCR4D84Hvariant (CXCR4D84H) using patient-derived peripheral blood mononuclear cells and in vitro cellular assaysshow decreased CXCR4 internalization and increased chemotaxis in response to CXCL12, similar to known CXCR4WHIM, but also revealed unique features of CXCR4D84H signaling to cAMP, Ca2+ mobilization and AKT/ERK pathways. These findings are consistent with molecular dynamics simulations that show disruption of the Na+ binding pocket by D84H, resulting in collapse of the hydrophobic gate above and destabilization of the inactive state of CXCR4. Mavorixafor, a CXCR4 antagonist being evaluated in clinical trials for chronic neutropenia and WHIM syndrome, normalized CXCL12-mediated chemotaxis of CXCR4D84H patient lymphocytes ex vivo and improved WBC and subset counts in 1 patient with CXCR4D84H enrolled in the chronic neutropenia phase 1b clinical trial (NCT04154488). The present study expands the current understanding of CXCR4 function and genotype-phenotype correlations in WHIM syndrome and in people with WHIM-like phenotypes.