CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives

França, Tábata Takahashi; Barreiros, Lucila Akune; al-Ramadi, Basel K.; Ochs, Hans D.; Cabral-Marques, Otávio; Condino‐Neto, Antônio

doi:10.1080/1744666x.2019.1573674

Cited by 36 publications

(34 citation statements)

References 111 publications

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“…CD40L is known to be required for generating primary cytotoxic T cells in viral infections [ 3 ]. Deficiency or mutation of CD40L causes severe immunodeficiency and X-linked Hyper-IgM syndrome [ 4 ]. It binds to CD40 expressed on antigen presenting cells (APCs) in the early phase of immunological synapse (IS) and acts to transmit co-stimulatory signals to both T cells and APCs, which in turn help B cells proliferate and differentiate into plasma cells [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Chrysophanol Mitigates T Cell Activation by Regulating the Expression of CD40 Ligand in Activated T Cells

Lee

Jeong

2020

IJMS

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Since T lymphocytes act as mediators between innate and acquired immunity, playing a crucial role in chronic inflammation, regulation of T cell activation to suitable levels is important. Chrysophanol, a member of the anthraquinone family, is known to possess several bioactivities, including anti-microbial, anti-cancer, and hepatoprotective activities, however, little information is available on the inhibitory effects of chrysophanol on T cell activation. To elucidate whether chrysophanol regulates the activity of T cells, IL-2 expression in activated Jurkat T cells pretreated with chrysophanol was assessed. We showed that chrysophanol is not cytotoxic to Jurkat T cells under culture conditions using RPMI (Rosewell Park Memorial Institute) medium. Pretreatment with chrysophanol inhibited IL-2 production in T cells stimulated by CD3/28 antibodies or SEE-loaded Raji B cells. We also demonstrated that chrysophanol suppressed the expression of the CD40 ligand (CD40L) in activated T cells, and uncontrolled conjugation between B cells by pretreatment with chrysophanol reduced T cell activation. Besides, treatment with chrysophanol of Jurkat T cells blocked the NFκB signaling pathway, resulting in the abrogation of MAPK (mitogen-activated protein kinase) in activated T cells. These results provide novel insights into the suppressive effect of chrysophanol on T cell activation through the regulation of CD40L expression in T cell receptor-mediated stimulation conditions.

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Section: Introductionmentioning

confidence: 99%

Chrysophanol Mitigates T Cell Activation by Regulating the Expression of CD40 Ligand in Activated T Cells

Lee

Jeong

2020

IJMS

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“…The patient was reported to have a heterozygous CD40LG gene mutation (c.511dupA), a frameshift mutation resulting in premature termination of the protein. CD40L dysfunction is one of the causes of rare primary immunodeficiency diseases accounting for 65-70% of HIGM1 cases (16)(17)(18). Hence, in P. jirovecii-infected children with or without PAP, immunodeficiency should be considered, and genetics analysis should be undertaken.…”

Section: Resultsmentioning

confidence: 99%

Pulmonary Alveolar Proteinosis Due to Pneumocystis carinii in Type 1 Hyper-IgM Syndrome: A Case Report

et al. 2020

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Background: Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease. Reports of rare cases of PAP due to Pneumocystis jirovecii (P. jirovecii) exist in infants with immunodeficiency diseases, but no cases have been reported to date in pediatric patients with type 1 hyper-IgM syndrome (HIGM1). Case Presentation: Herein, we present a case of PAP secondary to P. jirovecii on an infant with HIGM1. He was admitted to our unit because of cough and tachypnea. Lung biopsy confirmed the diagnosis of PAP, whereas hexamine-silver staining of the bronchoalveolar lavage fluid identified P. jirovecii infection. No other probable cause of PAP was observed. Whole exome sequencing indicated a novel c.511dupA (p.I171N * 30) hemizygous mutation in the CD40 ligand (CD40LG) gene. He was cured with bronchoalveolar lavage and compound sulfamethoxazole tablets. Conclusions: To our knowledge, this is the first reported case of P. jirovecii infection as a reversible cause of PAP in an infant with HIGM1.

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“…The morbidity and mortality associated with CD40L deficiency have resulted in treatment recommendations that focus on the prevention of infections with Ig replacement, antibiotic prophylaxis, and G‐CSF, with the only proposed curative therapy being HSCT 1 . Notably, the risk of unsuccessful HSCT has decreased in the past two decades due to the improvement in early diagnosis of CD40L deficiency 4 .…”

Section: Discussionmentioning

confidence: 99%

“…However, the impact of defective CD40L signaling is much broader, including a disrupted cellular response, coupled with reduced production of IFN‐γ cytokines and impaired generation of memory T and B cells, among other features. Unsurprisingly, given the important role of this molecule, individuals with CD40L‐deficiency present with diverse manifestations, including recurrent sinopulmonary bacterial infections, infections with opportunistic microorganisms, such as PJP and Cryptosporidium parvum (leading to chronic diarrhea), sclerosing cholangitis, and neutropenia as well as autoimmune manifestations 1 …”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell transplantation in CD40 ligand deficiency: A single‐center experience

Uygun

Karasu

et al. 2020

Pediatric Transplantation

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Deficiency of the CD40L, expressed on the surface of T lymphocytes, is caused by mutations in the glycoprotein CD40L (CD154) gene. Resulting defective humoral and cellular responses cause a clinical presentation that includes recurrent sinopulmonary bacterial infections, opportunistic infections, sclerosing cholangitis, neutropenia, and autoimmune manifestations. HSCT represents the only curative treatment modality. However, the therapeutic decision to use HSCT proves challenging in many cases, mainly due to the lack of a phenotype‐genotype correlation. We retrospectively reviewed patients with CD40L deficiency who were transplanted in Antalya and Göztepe MedicalPark Pediatric HSCT units from 2014 to 2019 and followed by Akdeniz University School of Medicine Department of Pediatric Immunology. The records of eight male cases, including one set of twins, were evaluated retrospectively. As two transplants each were performed on the twins, a total of ten transplants were evaluated. Conditioning regimens were predominantly based on myeloablative protocols, except for the twins, who received a non‐myeloablative regimen for their first transplantation. Median neutrophil and platelet engraftment days were 13 (range 10‐19) and 14 (range 10‐42) days, respectively. In seven of ten transplants, a CMV reactivation was developed without morbidity. None of the patients developed GVHD, except for one mild case of acute GVHD. All patients survived, and the median follow‐up was 852 days. Our data show that HSCT for patients with CD40 ligand deficiency is a potentially effective treatment for long‐term disease control.

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CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives

Cited by 36 publications

References 111 publications

Chrysophanol Mitigates T Cell Activation by Regulating the Expression of CD40 Ligand in Activated T Cells

Chrysophanol Mitigates T Cell Activation by Regulating the Expression of CD40 Ligand in Activated T Cells

Pulmonary Alveolar Proteinosis Due to Pneumocystis carinii in Type 1 Hyper-IgM Syndrome: A Case Report

Hematopoietic stem cell transplantation in CD40 ligand deficiency: A single‐center experience

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