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Since the first clinical description in 1952, immunoglobulin replacement therapy remains the mainstay of treatment of patients with X-linked agammaglobulinemia (XLA). However, this therapy only replaces IgG isotype and does not compensate for the loss of Bruton tyrosine kinase in non-B-lymphocytes. Patients may still therefore develop complications despite current standard of care. Here, we describe an XLA patient with persistent chronic norovirus infection, refractory to treatment and causing intestinal failure. The patient underwent haematopoietic stem cell transplantation, curing XLA and allowed clearance of norovirus prior to humoral immunoreconstitution, suggesting non-humoral immunodeficiency in these patients.

X-linked agammaglobulinemia is a rare primary immunodeficiency due to a BTK mutation. The patients are characteristically deficient in peripheral B cells and serum immunoglobulins. While they are susceptible to infections caused by bacteria, enteroviruses, and parasites, fungal infections are uncommon in XLA patients. Here, we report a boy of Malay ethnicity who suffered from recurrent upper respiratory tract infections and severe progressive necrotizing fasciitis caused by Saksenaea erythrospora. Immunological tests showed a B cell deficiency and hypogammaglobulinemia. Whole-exome sequencing identified a dinucleotide deletion (c.1580_1581del) in BTK, confirmed by Sanger sequencing and predicted to be disease causing by in silico functional prediction tools (Varsome and MutationTaster2) but was absent in the gnomAD database. This mutation resulted in a frameshift and premature termination (p.C527fs), which disrupted the protein structure. The mother was heterozygous at the mutation site, confirming her carrier status. Flow cytometric analysis of monocyte BTK expression showed it to be absent in the patient and bimodal in the mother. This study describes a novel BTK mutation in a defined hotspot and an atypical fungal phenotype in XLA. Further studies are required to understand the pathogenesis of fungal infection in XLA.

Introduction Influenza virus is a potential cause of severe disease in the immunocompromised. X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by the lack of immunoglobulin, B cells, and plasma cells, secondary to mutation in Bruton’s tyrosine kinase (Btk) gene. Btk is expressed in both B and dendritic cells (DC). However, little is known about the immune response of DC and T cells to influenza virus in XLA patients. Methods The in vitro maturation and antigen presenting function of monocyte-derived immature DC (imDC) from 12 XLA patients and 23 age-matched normal controls in response to influenza virus were examined. Influenza virus-specific CD4 and CD8 T cell responses in the patients and controls were further determined after administration of inactivated trivalent influenza vaccine. Results imDC from XLA patients had normal maturation based on major histocompatibility complex (MHC)-I, MHC-II, CD83 and CD86 expression, and interferon (IFN)-α and interleukin-12 production upon influenza virus stimulation. They also had a normal capacity to induce allogeneic T cell proliferation in response to influenza virus. TIV was well tolerated in XLA patients. Influenza virus-specific CD4+IFN-γ+ and CD8+ IFN-γ+ T cells and HLA-A2/M158–66-tetramer+ CTLs could be induced by TIV in XLA patients, and the levels and duration of maintaining these virus-specific cells in XLA patients are comparable to that in normal controls. Conclusion We demonstrated for the first time that XLA patients have fully competent DC and T cell immune responses to influenza virus. TIV is safe and could be an option for providing T cell-mediated protection against influenza virus infection in XLA patients.

X-linked agammaglobulinemia (XLA) is clinically characterized by recurrent bacterial infections during early infancy. Although it is not a phagocytic disorder, XLA is sometimes associated with neutropenia. We conducted a nation-wide survey to determine the frequency of neutropenia among Japanese XLA patients. Responses were received from 87 (86%) of 101 patients in which BTK mutations were previously identified, and of these, 16 (18%) had neutropenia. All episodes of neutropenia occurred before initiation of intravenous immunoglobulin (IVIG) replacement therapy. Two XLA patients died of multiple organ failure caused by severe neutropenia and Pseudomonas sepsis before initiation of IVIG replacement therapy. These results suggest that, in some cases, severe bacterial infections in XLA patients might be caused not only by antibody deficiencies but also by neutropenia.

X-linked agammaglobulinemia is caused by mutations in the BTK gene, which result in a precursor B-cell differentiation arrest in the bone marrow and the absence of or strongly reduced B lymphocytes in blood. We identified a patient with a mild clinical phenotype, low numbers of B lymphocytes, and a splice-site mutation in the BTK gene. The precursor B-cell compartment in the bone marrow of this patient was almost identical to that in healthy children. Using real-time quantitative polymerase chain reaction, we were able to detect low levels of wild-type BTK transcripts in his granulocytes. Therefore, we speculated that wild-type BTK transcripts might be responsible for a milder clinical and immunological phenotype, as has been shown in several other diseases. Consequently, we quantified the expression of wild-type BTK transcripts in granulocytes of eight additional patients with splice-site mutations and compared their phenotypes with 17 patients with other types of BTK mutations. In these eight patients, the presence of low levels of wild-type BTK transcripts did not show a clear correlation with the percentage, absolute number, or immunophenotype of B lymphocytes nor with age or serum immunoglobulin levels at diagnosis. Nevertheless, we postulate that the presence of wild-type BTK transcripts can be one of the many factors that influence the clinical and immunological phenotype in X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is caused by mutations in the gene encoding the cytoplasmic Bruton's tyrosine kinase (Btk). Btk has been shown to play an essential role in the development of B1 (CD5+) and conventional circulating mature B cells (B2) in mouse and man. It has been shown in earlier studies that Btk is involved in both the BCR- and CD40-mediated signaling pathways. In this study, we analyzed the responsiveness of Epstein-Barr virus (EBV) transformed B cells from nine XLA patients to CD40 stimulation, particularly the CD40 induced activation of c-Jun N-terminal kinase (JNK). In eight XLA patients the JNK activation was unimpaired and in one case INK could not be activated by anti-CD40 stimulation. Btk protein expression was detectable by Western blotting in six cases, in one case Btk expression was drastically reduced, and in three cases no Btk expression could be observed. Btk kinase activity was found in three cases and it was reduced in one and not detectable in five cases. Furthermore, in one female patient with an agammaglobulinemia, Btk expression and function as well as JNK activation by CD40 stimulation was unimpaired. Our findings demonstrate that INK activation via the CD40 signaling pathway is intact in EBV-transformed B cells of most if not all XLA patients, independent of the mutation and its effect on Btk expression and kinase activity. We suggest that Btk is not necessary for the activation of INK upon CD40 stimulation, at least in the B cell subpopulation we had studied. We cannot exclude that these B cells belong to a "leaky" B-cell subpopulation in which the CD40 signaling pathway has become independent of Btk function.

X-linked agammaglobulinemia (XLA) is clinically characterized by reduced number of peripheral B cells and diminished levels of serum immunoglobulins, and caused by a mutation in the Bruton’s tyrosine kinase (BTK) gene, which play a pivotal role in signal transduction of pre-B-cell receptor (BCR) and BCR. B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy in children, and it may be associated with gene alterations that regulate B-cell development. Here we described a first case of XLA associated BCP-ALL. The whole-exome sequencing revealed a somatic mutation in MLL2 in the sample from the onset of BCP-ALL. This study suggests that the alterations of BTK and MLL2 synergistically function as leukemogenesis.

The role of the Bruton tyrosine kinase (Btk) protein in neutrophil function has been evaluated using neutrophils from healthy volunteers after incubation with a Btk inhibitor, leflunomide metabolite analog (LFM-A13), suggesting an important role for Btk in neutrophil function. We sought to determine the role of Btk protein on neutrophil superoxide generation and chemotaxis stimulated by N-formyl-methionine-leucine-phenylalanine (fMLP).Chemotaxis was assayed on agarose gel and superoxide generation by cytochrome C reduction. The affects of LFM-A13 on chemotaxis and superoxide generation in unstimulated and fMLP stimulated neutrophils were studied in Btk deficient neutrophils from XLA patients compared with matched controls analyzed simultaneously.Chemotaxis and stimulated superoxide production were similar in the normal and Btk deficient neutrophils and were similarly inhibited by LFM-A13. In one patient, LFMA13 had no effect on superoxide generation in Btk deficient neutrophils up to a concentration of 25 microM, while inhibited superoxide production by control neutrophils.Our results suggest that Btk does not have a specific role in neutrophil fMLP-stimulated superoxide generation and chemotaxis since these activities were similarly inhibited by LFM-A13 in Btk deficient and normal neutrophils. The lack of superoxide generation following Btk inhibition by LFM-A13 in Btk deficient neutrophils from one patient may suggest some heterogeneity in the role of Btk in fMLP induced neutrophil superoxide generation.

To evaluate the lipopolysaccharide (LPS)-induced pro-inflammatory cytokine response by peripheral blood mononuclear cells (PBMCs) from XLA patients. Thirteen patients with XLA were included in the study. LPS-induced TNF-α, IL-1β, IL-6, and IL-10 production was determined in PBMCs from patients and matched healthy controls by ELISA. Cytokine production was correlated with the severity of mutation, affected domain and clinical characteristics. In response to LPS, PBMCs from XLA patients produced significantly higher amounts of pro-inflammatory cytokines and IL-10 compared to controls, and this production was influenced neither by the severity of the mutation nor the affected domain. PBMCs from patients with a history of more hospital admissions before their diagnosis produced higher levels of TNF-α. PBMCs from patients with lower serum IgA levels showed a higher production of TNF-α and IL-1β. Less severe (punctual) mutations in the Btk gene were associated with higher serum IgG levels at diagnosis. Our results demonstrate a predominantly inflammatory response in XLA patients after LPS stimulation and suggest a deregulation of TLR signaling in the absence of Btk. This response may be influenced by environmental factors.

X-linked agammagobulinemia (XLA) is a primary immunodeficiency disorder caused by Bruton's tyrosine kinase (Btk) gene mutation. Recent studies suggested genotype-phenotype correlation in XLA, but a definitive association remains controversial. We examined the relationship between specific Btk gene mutations and severity of clinical presentation in 62 patients with XLA. Disease severity was assessed by the age of disease onset and the presence of severe infections, while mutations were classified into severe and mild based on structural and functional consequence by bioinformatics analysis. Fifty-six Btk mutations were identified in 62 patients from 57 kindreds. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset as well as occurrence of severe infections. A critical analysis of the circumstances upon presentation also revealed that under-recognition of recurrent infections and relevant family history are important hurdles to timely diagnosis of XLA.

X-Linked agammaglobulinemia is a prototypical humoral immunodeficiency with the mutation of the Bruton's tyrosine kinase gene.We investigated the gene mutation and clinical features of 30 Chinese X-linked agammaglobulinemia (XLA) patients from 27 families. There were 26 mutations, including 11 novel and 15 recurrent mutations, distributing over the entire gene. The nucleotide and amino acid aberration, 1129CT(H333Y) and 1196TA(I355N), in SH2 have not been reported before. Five (I355N, W124R, R520X, I590F, G594E) of the 24 mutations not detected in the mothers receiving gene analysis were determined to be de novo. Two mutations occurred within intronic splice-site sequences (intron5(-2)AG, intron17(-2)AT).There are eight mutations in the PH domain, two mutations in the SH3 domain, three mutations in the SH2 domain, one mutation in the TH domain, and other 16 mutations in the TK domain. The mutations of protein domain is most common in TK (53%) domain and then in PH(8%) domain. Missense and nonsense mutations were found equal in 46% of the detected mutations. All of the patients are alive, but one died of liver cancer. Clinical features and serum Igs levels range variedly and were not correlated with genotypes. Our results demonstrated molecular genetic characteristics of XLA in mainland China.

X-linked agammaglobulinemia (XLA) is characterized by low levels of B-lymphocytes with early-onset, recurrent, microbial infections occasionally causing neurological symptoms. We observed an atypical clinical course of XLA, complicated since early childhood with neurological impairment, progressive sensorineural deafness, and dystonia in six boys of four unrelated families. The neurologic symptoms suggested the diagnosis of Mohr-Tranebjaerg syndrome, caused by mutations in the TIMM8A gene, previously known as DDP1, and located centromerically of BTK. Deafness dystonia peptide (DDP1) participates in neurological development and is a part of the mitochondrial protein import pathway. Mutation analysis of the BTK gene revealed gross deletions of different lengths in all patients, in one case extending approximately 196 kb, including the genes TIMM8A, TAF7L, and DRP2. The most prominent clinical findings of this contiguous deletion syndrome are the combination of immunodeficiency and sensorineural deafness, which were present in all affected boys. The severity of symptoms, however, did not correlate with the extent of the deletion.