Profound Lymphopenia Research Articles

Sheep lung segmental delivery strategy demonstrates adenovirus priming of local lung responses to bacterial LPS and the role of elafin as a response modulator.

Viral lung infections increase susceptibility to subsequent bacterial infection. We questioned whether local lung administration of recombinant adenoviral vectors in the sheep would alter the susceptibility of the lung to subsequent challenge with bacterial lipopolysaccharide (LPS). We further questioned whether local lung expression of elafin, a locally produced alarm anti-LPS/anti-bacterial molecule, would modulate the challenge response. We established that adenoviral vector treatment primed the lung for an enhanced response to bacterial LPS. Whereas this local effect appeared to be independent of the transgene used (Ad-o-elafin or Ad-GFP), Ad-o-elafin treated sheep demonstrated a more profound lymphopenia in response to local lung administration of LPS. The local influence of elafin in modulating the response to LPS was restricted to maintaining neutrophil myeloperoxidase activity, and levels of alveolar macrophage and neutrophil phagocytosis at higher levels post-LPS. Adenoviral vector-bacterial synergism exists in the ovine lung and elafin expression modulates such synergism both locally and systemically.

Mutations in tetratricopeptide repeat domain 7A (TTC7A) are associated with combined immunodeficiency with dendriform lung ossification but no intestinal atresia

Introduction: Genetic aberrations associated with combined immunodeficiency have been increasingly identified in the past two decades. Yet, there are still 30% of these patients with unidentified genetic cause.Methods: We employed whole genome sequencing to identify the genetic defect leading to combined immunodeficiency. Thymus, gut, and lung tissues were studied using hematoxylin and eosin staining as well as immunohistochemistry.Results: We identified 2 deleterious mutations in the TTC7A gene. Surprisingly, the patient did not have intestinal atresia but suffered repeated infections as well fatal pneumonitis. Dendriform lung ossification developed, which was unique to this case. The patient had typical presentation of combined immunodeficiency including profound lymphopenia, markedly reduced in-vitro response to mitogens, as well as low TRECS. Serum immunoglobulins were also markedly reduced.Conclusion: Mutations in the TTC7A gene can cause combined immunodeficiency with no intestinal atresia and predispose to lung ossification.Statement of novelty: TTC7A mutations can cause profound immunodeficiency without multiple intestinal atresia. We report here for the first time that this defect is associated with dendriform lung ossification.

Efficacy of recombinant human interleukin 7 in a patient with severe lymphopenia-related progressive multifocal leukoencephalopathy.

In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy. Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement.

Low levels of SDF-1α constrain DC recovery and diminish homeostatic proliferation of naïve CD4+ T cells during graft-versus-host disease. (TRAN3P.892)

Abstract Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (SCT) and its effect on T cell regeneration greatly increases the immunodeficiency normally associated with SCT. As a result, GVHD patients experience profound lymphopenia and lymphocyte reconstitution takes generally several months or years. The goal of this work was to assess the impact of GVHD on homeostatic proliferation (HP) of non-alloreactive naïve CD4+ T lymphocytes with the hypothesis that regeneration of the peripheral niche permissive to CD4 HP is constrained by GVHD. To study the impact of GVHD on the peripheral niche regulating CD4 HP, we used a Parent→F1 mouse model and observed a complete abrogation of CD4 HP in GVHD hosts. Loss of HP was related to depletion of all DC subsets as well as low levels of IL-7. While Flt3-ligand (FL) levels were normal, Stromal Derived Factor-1α (SDF-1α) was significantly diminished in GVHD mice. Administration of FL or SDF-1α significantly increased DC counts but CD4 HP was restored only when FL or SDF-1α was combined to IL-7. Importantly, while FL treatment aggravated GVHD, GVHD was improved by SDF-1α therapy. Our study shows that lack of immune reconstitution of CD4+ T cells is primarily due to failure of DC recovery owing to diminished SDF-1α production and diminished IL-7 and that the combination of SDF-1α and IL-7 could be used to enhance CD4 HP in GVHD hosts.

Dynamin 2–dependent endocytosis is required for sustained S1PR1 signaling

Sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) is critical for lymphocyte egress from lymphoid organs. Lymphocytes encounter low S1P concentrations near exit sites before transmigration, yet S1PR1 signaling is rapidly terminated after exposure to S1P. How lymphocytes maintain S1PR1 signaling in a low S1P environment near egress sites is unknown. Here we identify dynamin 2, an essential component of endocytosis, as a novel regulator of T cell egress. Mice with T cell-specific dynamin 2 deficiency had profound lymphopenia and impaired egress from lymphoid organs. Dynamin 2 deficiency caused impaired egress through regulation of S1PR1 signaling, and transgenic S1PR1 overexpression rescued egress in dynamin 2 knockout mice. In low S1P concentrations, dynamin 2 was essential for S1PR1 internalization, which enabled continuous S1PR1 signaling and promoted egress from both thymus and lymph nodes. In contrast, dynamin 2-deficient cells were only capable of a pulse of S1PR1 signaling, which was insufficient for egress. Our results suggest a possible mechanism by which T lymphocytes positioned at exit portals sense low S1P concentrations, promoting their egress into circulatory fluids.

CXCR4-related increase of circulating human lymphoid progenitors after allogeneic hematopoietic stem cell transplantation.

Immune recovery after profound lymphopenia is a major challenge in many clinical situations, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recovery depends, in a first step, on hematopoietic lymphoid progenitors production in the bone marrow (BM). In this study, we characterized CD34+Lin−CD10+ lymphoid progenitors in the peripheral blood of allo-HSCT patients. Our data demonstrate a strong recovery of this population 3 months after transplantation. This rebound was abolished in patients who developed acute graft-versus-host disease (aGVHD). A similar recovery profile was found for both CD24+ and CD24− progenitor subpopulations. CD34+lin−CD10+CD24− lymphoid progenitors sorted from allo-HSCT patients preserved their T cell potentiel according to in vitro T-cell differentiation assay and the expression profile of 22 genes involved in T-cell differentiation and homing. CD34+lin−CD10+CD24− cells from patients without aGVHD had reduced CXCR4 gene expression, consistent with an enhanced egress from the BM. CCR7 gene expression was reduced in patients after allo-HSCT, as were its ligands CCL21 and CCL19. This reduction was particularly marked in patients with aGVHD, suggesting a possible impact on thymic homing. Thus, the data presented here identify this population as an important early step in T cell reconstitution in humans and so, an important target when seeking to enhance immune reconstitution.

The Genotoxin Colibactin Exacerbates Lymphopenia and Decreases Survival Rate in Mice Infected With Septicemic Escherichia coli

Sepsis is a life-threatening infection. Escherichia coli is the first known cause of bacteremia leading to sepsis. Lymphopenia was shown to predict bacteremia better than conventional markers of infection. The pks genomic island, which is harbored by extraintestinal pathogenic E. coli (ExPEC) and encodes the genotoxin colibactin, is epidemiologically associated with bacteremia. To investigate a possible relationship between colibactin and lymphopenia, we examined the effects of transient infection of lymphocytes with bacteria that were and those that were not producing the genotoxin. A mouse model of sepsis was used to compare the virulence of a clinical ExPEC isolate with its isogenic mutant impaired for the production of colibactin. We observed that colibactin induced double-strand breaks in the DNA of infected lymphocytes, leading to cell cycle arrest and to cell death by apoptosis. E. coli producing colibactin induced a more profound lymphopenia in septicemic mice, compared with the isogenic mutant unable to produce colibactin. In a sepsis model in which the mice were treated by rehydration and antibiotics, the production of colibactin by the bacteria was associated with a significantly lower survival rate. In conclusion, we demonstrate that production of colibactin by E. coli exacerbates lymphopenia associated with septicemia and could impair the chances to survive sepsis.

Reduction in radiation‐induced lymphocytopenia by famotidine in patients undergoing radiotherapy for prostate cancer

Ionizing radiation causes a series of hematological alterations especially profound lymphocytopenia during and after the radiotherapy course. To investigate whether famotidine can reduce hematologic toxicity in patients treated with radiotherapy for prostate cancer. A total of 36 patients undergoing radiotherapy for prostate cancer were randomized to receive either placebo or famotidine tablets. Participants were pretreated with 40 mg of oral famotidine or placebo tablets twice daily, 4 and 3 hr before each radiotherapy fraction. The patients received external-beam radiotherapy up to 70 Gy. Complete blood counts with differential, platelet counts, and hemoglobin levels were obtained at baseline, biweekly during the treatment and once 4 weeks after the end of radiotherapy course. Magnitude of changes from baseline in the hematological parameters was determined and compared using Repeated Measures ANOVA. Famotidine was well tolerated. A total of 112 blood samples were evaluated. A significant reduction in radiation-induced lymphocytopenia was noted in patients receiving famotidine than in patients receiving placebo (P = 0.006). No significant difference was observed between two groups for the decline in platelets, erythrocytes and leucocytes. For both groups, neutrophil, monocyte, eosinophil, and hemoglobin levels did not change significantly during the treatment. Our results indicate that famotidine could result in a significant reduction in radiation-induced lymphocytopenia and may consequently increase radiotherapy efficacy as well as survival times. This radioprotective effect may be chiefly associated with its antioxidant and radical scavenging properties. Further studies are required to confirm these encouraging results.

Idiopathic CD4 Lymphocytopenia Manifesting as Refractory Genital Dysplasia

Idiopathic CD4 lymphocytopenia is an immunodeficiency disorder with low absolute CD4 T-lymphocyte count with no evidence of human immunodeficiency virus or other known cause. A 22-year-old woman presented with a high-grade Pap test result. Work-up demonstrated cervical intraepithelial neoplasia 3 and vaginal intraepithelial neoplasia 3 with extensive condyloma. She presented 6 months after her initial treatment with recurrent disease and was referred to the immunology department, where she was found to have profound lymphopenia. After further evaluation, idiopathic CD4 lymphocytopenia was diagnosed. Idiopathic CD4 lymphocytopenia is a rare acquired immunodeficiency. Although genital dysplasia is common in young women, this case demonstrates the importance of determining other etiologies of recurrent human papillomavirus infections and possible immunodeficiencies that may affect management and outcomes.

Newborn screening for severe combined immunodeficiency: an opportunity for intervention

Severe combined immunodeficiency (SCID) is a potentially fatal disorder characterized by defective T- and B-lymphocyte function. We describe a 34-week female twin who had developed feeding intolerance, perioral cyanosis, abdominal distension and neutropenia at 1 month of age. Despite several evaluations including an 'inconclusive' newborn screening result for SCID, the presence of profound lymphopenia was unappreciated. Eventually a diagnosis of SCID in association with adenosine deaminase deficiency was made. This case serves to emphasize the importance of newborn screening for SCID in the context of careful evaluation of clinical and laboratory findings that may be overlooked and result in a delay in the diagnosis of a potentially life-threatening condition.

Myeloablative Temozolomide Enhances CD8+ T-Cell Responses to Vaccine and Is Required for Efficacy against Brain Tumors in Mice

Temozolomide (TMZ) is an alkylating agent shown to prolong survival in patients with high grade glioma and is routinely used to treat melanoma brain metastases. A prominent side effect of TMZ is induction of profound lymphopenia, which some suggest may be incompatible with immunotherapy. Conversely, it has been proposed that recovery from chemotherapy-induced lymphopenia may actually be exploited to potentiate T-cell responses. Here, we report the first demonstration of TMZ as an immune host-conditioning regimen in an experimental model of brain tumor and examine its impact on antitumor efficacy of a well-characterized peptide vaccine. Our results show that high-dose, myeloablative (MA) TMZ resulted in markedly reduced CD4+, CD8+ T-cell and CD4+Foxp3+ TReg counts. Adoptive transfer of naïve CD8+ T cells and vaccination in this setting led to an approximately 70-fold expansion of antigen-specific CD8+ T cells over controls. Ex vivo analysis of effector functions revealed significantly enhanced levels of pro-inflammatory cytokine secretion from mice receiving MA TMZ when compared to those treated with a lower lymphodepletive, non-myeloablative (NMA) dose. Importantly, MA TMZ, but not NMA TMZ was uniquely associated with an elevation of endogenous IL-2 serum levels, which we also show was required for optimal T-cell expansion. Accordingly, in a murine model of established intracerebral tumor, vaccination-induced immunity in the setting of MA TMZ–but not lymphodepletive, NMA TMZ–led to significantly prolonged survival. Overall, these results may be used to leverage the side-effects of a clinically-approved chemotherapy and should be considered in future study design of immune-based treatments for brain tumors.

Cernunnos Deficiency Reduces Thymocyte Life Span and Alters the T Cell Repertoire in Mice and Humans

Cernunnos is a DNA repair factor of the nonhomologous end-joining machinery. Its deficiency in humans causes radiosensitive severe combined immune deficiency (SCID) with microcephaly, characterized in part by a profound lymphopenia. In contrast to the human condition, the immune system of Cernunnos knockout (KO) mice is not overwhelmingly affected. In particular, Cernunnos is dispensable during V(D)J recombination in lymphoid cells. Nevertheless, the viability of thymocytes is reduced in Cernunnos KO mice, owing to the chronic activation of a P53-dependent DNA damage response. This translates into a qualitative alteration of the T cell repertoire to one in which the most distal Vα and Jα segments are missing. This results in the contraction of discrete T cell populations, such as invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cells, in both humans and mice.

Disseminated Aspergillosis in Adult-Onset Severe Combined Immunodeficiency: A Case of Xcind Syndrome

M O N D A Y 544 Disseminated Aspergillosis in Adult-Onset Severe Combined Immunodeficiency: A Case of Xcind Syndrome Kellie J. Lim, MD, E. Richard Stiehm, MD, FAAAAI, Richard Gatti, MD, Otto Yang, MD; UCLA, Department of Pediatrics, Division of Allergy and Immunology, Los Angeles, CA, Division of Allergy and Immunology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, UCLA, Department of Pathology & Laboratory Medicine, UCLA, Department of Medicine, Division of Infectious Disease. RATIONALE: The onset and diagnosis of severe combined immunodeficiency (SCID) typically occurs in infancy; however, in rare cases it is diagnosed in adulthood. A 24 year old male of normal intelligence presented with a seizure and was later diagnosed with disseminated aspergillosis with intracranial and pulmonary involvement. He had profound CD4 lymphopenia and subsequently developed hypogammaglobulinemia. He did not have history of recurrent infections and was previously in good health. Physical findings included dysmorphic facies, short stature, and microcephaly; thus radiosensitivity syndromes were considered. METHODS: Colony survival assay (CSA), Western blots, and DNA sequencing were performed. RESULTS: CSA confirmed radiosensitivity. Western blots were performed for genes associated with double-stranded DNA breakage repair, and they were normal for: ATM (ataxia telangiectasia), NBS (Nijmegen breakage syndrome), FANCD2 (Fanconi anemia), APTX (ataxia-oculomotor apraxia syndrome), Artemis (Omenn syndrome and Athabascan-type severe combined immunodeficiency), PNPK, MRE11, and RAD50. Antibody for DNA ligase IVon fibroblast lysates prepared in RIPA buffer failed to detect DNA ligase IV. DNA sequencing of DNA ligase IV did not reveal mutations. CONCLUSIONS: DNA ligase IV deficiency is an XCIND syndrome: X-ray-irradiation sensitivity, Cancer susceptibility, Immunodeficiency, Neurological abnormalities, and Double-strand DNA breakage. DNA ligase IV plays a major role in non-homologous end joining (NHEJ) and is also involved in physiological V(D)J rearrangement and class switching, thereby leading to immunodeficiency when a mutation occurs.

Excellent Outcome of Concomitant Intensive Immunosuppression and Eculizumab in Aplastic Anemia/Paroxysmal Nocturnal Hemoglobinuria Syndrome

A 21 year men was referred to our Institution in 2007 for mild cytopenia and laboratory signs of hemolysis (Figure 1); based on flow cytometry, the diagnosis of PNH in the context of moderate AA was made. The patient did not receive any etiologic treatment until March 2009, when he started eculizumab because of severe anemia due to overt symptomatic hemolysis. The patient had no benefit from anticomplement treatment, with increasing transfusional need; after 3 months, the diagnosis of severe AA was documented. In absence of a suitable donor, Immunosuppressive Treatment (IST) was chosen as etiologic treatment [6]; the patients was enrolled in the trial NCT00895739 [7], which investigated the anti-CD52 alemtuzumab and cyclosporine A (CyA) as an alternative IST for AA. Given the persistent major PNH population, we decided to not discontinue eculizumab to minimize the risk of massive intravascular hemolysis and possible thrombotic complications. Alemtuzumab was administered subcutaneously (3-10-30-30 mg in 4 consecutive days), without relevant side effect. Irrespective of eculizumab, immediate and profound lymphocytopenia (absolute lymphocyte count <50/μL) was observed, as in patients not receiving alemtuzumab [7]. The IST resulted in a substantial increase of neutrophil, reticulocyte and platelet counts, with the best hematological response achieved at 4 months from treatment. Unfortunately, in the following months, irrespective of chronic CyA maintenance, blood counts felt down, thus the relapse of SAA prompted us to consider a second-line treatment. Given that the best unrelated donor was 5/6 HLA matched, we opted for a second course of IST using the rabbit Anti-Thymocyte Globuline (r-ATG) associated with CyA. The treatment was completed as scheduled (3.75 mg/kg for 5 days) without any side effect, and again lymphocyte depletion was observed irrespective of continuous eculizumab treatment. After this second IST the patient experienced progressive improvement of his blood counts, finally resulting in complete response (Figure 1). Notably, reappearance of intravascular hemolysis required transient increase of eculizumab dosage; with the progressive reduction of the PNH population, eculizumab was tapered to the standard dosage. The patient now shows normal blood counts, in absence of maintenance CyA treatment and without any sign or symptom of hemolysis.

Pneumocystis pneumonia during primary HIV infection: a case report and review of the literature

More than 90% of cases of pneumocystis pneumonia (PCP) in adults occur in patients with chronic HIV infection with CD4 counts lower than 200 cells/ml. Even though primary HIV infection can cause transient profound CD4 lymphocytopenia, PCP is rarely reported during primary HIV infection. We report a case of a 26-year-old man who was diagnosed with PCP in the setting of primary HIV infection. He was successfully treated with a 21-day course of oral co-trimoxazole.

Clinical and immunophenotypic features of atypical complete DiGeorge syndrome

DiGeorge syndrome is a congenital malformation characterized by variable defects of the thymus, heart and parathyroid glands. Athymic patients are classified as exhibiting complete DiGeorge syndrome. Some of these patients may also exhibit oligoclonal T-cell expansion, generalized rash and lymphadenopathy at some point after birth. This rare condition is known as atypical complete DiGeorge syndrome, resembles Omenn syndrome, and has not been fully characterized. The clinical and immunophenotypic features of atypical complete DiGeorge syndrome were assessed in two affected Japanese infants. T-cell receptor (TCR) Vβ repertoire was analyzed on flow cytometry and complementarity-determining region 3 spectratyping. Both patients had no detectable thymus tissue and profound T-cell lymphopenia soon after birth. Progressive increase of activated T cells, however, as well as eosinophilia, high serum IgE level, generalized rash, and lymphadenopathy were observed during early infancy. A highly restricted TCR Vβ repertoire was demonstrated both in CD4(+) and CD8(+) T cells. The Omenn syndrome-like manifestations might be associated with the oligoclonal proliferation of activated T cells. Analysis of the immunophenotype and TCR Vβ repertoire is helpful to establish the early diagnosis of atypical complete DiGeorge syndrome.

Profound CD4+ T lymphocytopenia in human immunodeficiency virus negative individuals, improved with anti-human herpes virus treatment

Lymphocytopenia and CD4+ T lymphocytopenia can be associated with many bacterial, fungal, parasite and viral infections. They can also be found in autoimmune and neoplastic diseases, common variable immunodeficiency syndrome, physical, psychological and traumatic stress, malnutrition and immunosuppressive therapy. Besides, they can also be brought into relation, without a known cause, with idiopathic CD4+ T lymphocytopenia. Among viral infections, the Retrovirus, specially the human immunodeficiency virus, is the most frequently cause. However, many acute viral infections, including cytomegalovirus and Epstein Barr virus can be associated with transient lymphocytopenia and CD4+ T lymphocytopenia. As is well known, transient lymphocytopenia and CD4+ T lymphocytopenia are temporary and overcome when the disease improves. Nonetheless, severe CD4+ T Lymphocytopenia associated with chronic infections by human herpes virus has not been reported. We describe 6 cases of human immunodeficiency virus negative patients, with chronic cytomegalovirus and Epstein Barr virus infections and profound lymphocytopenia with clinical symptoms of cellular immunodeficiency. These patients improved rapidly with ganciclovir or valganciclovir treatment. We claim here that it is important to consider the chronic human herpes virus infection in the differential diagnosis of profoundly CD4+ T lymphocytopenia etiology, when human immunodeficiency virus is absent, in order to start effective treatment and to determine, in future studies, the impact of chronic human herpes virus infection in human beings' health.

Absolute counts of peripheral blood leukocyte subpopulations in intraabdominal sepsis and pneumonia-derived sepsis: a pilot study

The leading pathophysiological changes during sepsis include systemic abnormalities in the immune response. Due to the general character of these disturbances, sepsis is usually studied as a homogenous clinical condition. We aimed to compare the immune response in intraabdominal sepsis (IAS) and pneumonia-derived sepsis (PDS). The following cell populations were examined: white blood cell count (WBC), monocytes, lymphocytes:CD3⁺, CD4⁺ and CD8⁺ T cells, B cells, and NK cells. In both studied groups (i.e. IAS and PDS), the WBC was elevated. However, it was significantly higher in the IAS group than in the PDS group. The difference was due to a lower granulocyte count, as well as a lower monocyte count in PDS. We found no significant correlation between the total lymphocyte number and CD3⁺CD8⁺ T cells in either form of sepsis. Similarly, we observed no correlation between the total lymphocyte number and the NK cells subset in IAS. However, the numbers of CD3⁺CD8⁺ and NK cells correlated similarly in both types of sepsis. Both studied types of sepsis induced profound lymphocytopenia, with marked loss of CD8⁺ T cells and the NK cells. However, the similarrelation between them, which was independent of the infection type, suggests that the NK and CD3⁺CD8⁺ cellshave shared mechanisms of regulation. The primary site of infection has an impact on the global immune reaction. These alternations include especially myeloid cells: granulocytes and monocytes which disappear from peripheral blood during PDS, but increase in IAS.

Dynamin 2 regulates S1P1 signalling and T cell migration (173.15)

Abstract Sphingosine 1-phosphate (S1P) is essential for T cell egress from lymphoid tissues by acting on its receptor S1P1. S1P agonism on S1P receptors is now used to treat autoimmune diseases by sequestering lymphocytes in lymphoid organs. However, not much is known about molecules that mediate T cell egress downstream of S1P1. Dynamin 2 is a large GTPase that is required for vesicle scission during endocytosis. Mice with a T cell-specific deletion of dynamin 2 had profound lymphopenia and an accumulation of mature thymocytes. Intrathymic dye injection revealed that thymic egress was inhibited in the absence of dynamin 2. Dynamin 2 regulated T cell migration downstream of S1P-S1P1 since dynamin 2-deficient thymocytes did not migrate in response to S1P in vitro. This was not due to a general defect in cell motility because T cells lacking dynamin 2 had a normal migratory response to CCL21. Dynamin 2 was required for ligand-induced S1P1 downmodulation, consistent with its known function in receptor-mediated endocytosis. In addition, dynamin 2 knockout thymocytes co-expressed S1P1 and CD69 on the cell surface demonstrating impaired S1P1 signalling in vivo. Surprisingly, the critical role of dynamin 2 in S1P1 signalling was independent of receptor internalization. Instead, dynamin 2-deficient T cells showed faster desensitization of S1P1 after agonist stimulation in vitro. Our data reveal an unexpected role for dynamin 2 in promoting T cell egress by regulating S1P1 signalling.

Ataxia-Telangiectasia Presenting With a Novel Immunodeficiency

Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, and variable degrees of immunodeficiency. Immunologic evaluations of affected patients often reveal anomalies of humoral and cell-mediated immunity. We describe a case of ataxia-telangiectasia with an atypical immunodeficiency and a novel mutation in the ATM gene. The patient presented at age 3 years with a perineal cellulitis associated with profound neutropenia and T-cell lymphopenia. Serum immunoglobulin levels and antibody titers were normal. Neurologic evaluation revealed minimal hypotonia and wide-based gait, without other signs of cerebellar dysfunction. The alpha-fetoprotein level was elevated, and molecular genetic testing confirmed the diagnosis of ataxia-telangiectasia, uncovering a novel ATM gene mutation c.3931C>T (p.Gln1311X) in exon 28. This patient presents a unique immunologic pattern with normal immunoglobulin levels, significant lymphopenia, and profound neutropenia. The diagnosis of ataxia-telangiectasia should be considered in children presenting with gait disorder and immunologic defects, regardless of subtype and severity.