X-Linked Agammaglobulinemia

Conley, Mary Ellen; Rohrer, Jurg; Minegishi, Yoshiyuki

doi:10.1385/criai:19:2:183

Cited by 110 publications

(57 citation statements)

References 115 publications

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“…10,11,37 Thus, failure to express CD40L results in impaired T-cell function and increases the risk for opportunistic infections and malignancy. [12][13][14] Therefore, unlike pure humoral immune deficiencies associated with mutations in Bruton's tyrosine kinase 38,39 or activation-induced cytidine deaminase, 40,41 ␥ globulin replacement therapy (IVIG) is less satisfactory for the management of XHM because of the significant T-cell abnormalities. 13,16 Despite ␥ globulin substitution therapy the expected survival rate for XHM is Ͻ 20% by the age of 25, emphasizing the need for new medical therapies for this disorder.…”

Section: Discussionmentioning

confidence: 99%

Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand

Jain

Kovacs

Nelson

et al. 2011

Blood

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X-linked hyper IgM syndrome (XHM) is a combined immune deficiency disorder caused by genetic alterations in CD40ligand. The purpose of this study was to investigate the safety and efficacy of recombinant CD40 ligand (rCD40L) in the treatment of the disease. Three children were administered rCD40L subcutaneously 3 times per week at 0.03 mg/kg for 22 weeks, and after a 12-week drug-free interval, the dose was increased to 0.05 mg/kg for an additional 22 weeks of treatment. Although specific antibody responses to T cell-dependent antigens was lacking, administration of rCD40 resulted in acquisition of the capacity to mount cutaneous delayed type hypersensitivity reactions that disappeared during the drug-free interval as well as the postbiologic follow-up period. [1][2][3] The cognate interaction between CD40L expressed on activated CD4 ϩ T cells and CD40 expressed constitutively on B cells leads to B-cell proliferation, somatic hypermutation in the immunoglobulin variable region, and immunoglobulin class switch recombination from IgM to IgG, IgA, and IgE. [4][5][6] Humans with mutations in the genes encoding CD40L have skewed IgM antibody responses and a markedly diminished or absent IgG response to protein antigens. 7-9 CD40 engagement on the surface of dendritic cells also influences dendritic cell maturation and activation. 8,10 It thus promotes the expression of factors that promote T-cell priming such as costimulatory molecules B7.1 (CD80) and B7.2 (CD86), IL-12 secretion, and the release of chemokines. 10,11 Indeed, humans and mice with CD40L deficiency exhibit defective T-cell function that manifests by a marked predisposition to develop opportunistic infections with Pneumocystis jerovici, Toxoplasma gondii, and Cryptosporidium species as well as an increased tendency to develop malignancies. [12][13][14][15] The IgG/IgA deficiency and associated humoral immune abnormalities in patients with XHM is effectively controlled by ␥ globulin replacement therapy (intravenous immunoglobulin [IVIG] therapy). 13,16 However, despite such treatment, the majority of patients die in the second decade of life as a consequence of impaired T-cell function. 13,17 Bone marrow transplantation is an effective treatment for patients with XHM, especially if performed early in life before the onset of secondary opportunistic infection, 18,19 although the need for matched related donors and the associated morbidity and mortality of the transplant impact on its clinical application. 20,21 Identification of CD40L as an important signaling molecule led to the development of a soluble form of recombinant CD40 ligand (rCD40L) that could be used in various clinical situations. 22,23 This trimeric form of human rCD40L was generated using an isoleucine zipper that is capable of activating the CD40 receptor (Amgen). We first conducted preclinical studies in a murine model of XHM in which the CD40 ligand was disrupted through genetic engineering revealed that administration of CD40 agonists or recombinant murine CD40L trimer reversed the c...

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Section: Discussionmentioning

confidence: 99%

Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand

Jain

Kovacs

Nelson

et al. 2011

Blood

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“…6 The molecular basis of this disorder is mutations in Bruton tyrosine kinase (btk) gene, whose malfunction leads to an arrest of B-cell differentiation. [7][8][9][10] This tyrosine kinase is expressed in myeloid cells as well as in B-lineage cells, but the effects of mutations in Btk appear to have no clinically significant effects on myeloid cell function. 11 It has been suggested that B lymphocytes not only are involved in humoral immune response, but may also have a role in influencing different facets of T-cell immunity.…”

Section: Introductionmentioning

confidence: 99%

Long-lasting memory-resting and memory-effector CD4+T cells in human X-linked agammaglobulinemia

Paroli

Accapezzato

Francavilla

et al. 2002

Blood

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“…X-linked agammaglobulinemia (XLA) is categorized as one of the primary immunodeficiency diseases which are characterized by a defect in the development of B lymphocytes, extreme hypogammaglobulinemia, and marked deficiency in the formation of the antibodies and their functions [1][2][3]. A mutation in the gene for Blymphocyte tyrosine kinase, known as the Btk Gene, is the cause of this disease [1][2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…A mutation in the gene for Blymphocyte tyrosine kinase, known as the Btk Gene, is the cause of this disease [1][2][3][4][5][6]. Patients affected by this disease are highly susceptible to infections, especially caused by Haemophilus influenzae, Pneumococcus, Giardia lamblia and Enteroviruses [4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

X-linked Agammaglobulinemia - Is it Really Rare?

Pasha¹,

Zhang²,

Hui-Ma³

et al. 2018

Clin Pediatr OA

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Background: X-Linked Agammaglobulinemia is a disease of the immune system in which there is defective development of the B lymphocytes due to which the production of gammaglobulins is markedly reduced; which results in immunodeficiency and high vulnerability to contract fatal infections. This is the reason for which a patient with XLA presents with history of recurrent infections. XLA is known to be caused due to a mutation in the Btk gene. Btk gene mutation observed on gene mapping markedly reduced levels of B lymphocytes and immunoglobulins; are the confirmatory laboratory findings for the diagnosis of XLA. As there is immunodeficiency in the patient, this condition is treated with intravenous immunoglobulin therapy. In this article, two cases with XLA have been described. Over a period of one month, two cases of XLA were admitted at the hospital. This is to pay attention to the fact that XLA is a rare condition, accounting to 1 in 200,000 live births. In view of its rarity, the two cases have been reported ahead in the article.

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X-Linked Agammaglobulinemia

Cited by 110 publications

References 115 publications

Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand

Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand

Long-lasting memory-resting and memory-effector CD4+T cells in human X-linked agammaglobulinemia

X-linked Agammaglobulinemia - Is it Really Rare?

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