Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors

Zonios, Dimitrios I.; Falloon, Judith; Bennett, John E.; Shaw, Pamela A.; Chaitt, Doreen G.; Baseler, Michael; Adelsberger, Joseph W.; Metcalf, Julia A.; Polis, Michael A.; Kovacs, Stephen J.; Kovács, J.; Davey, Richard T.; Lane, H. Clifford; Masur, Henry; Sereti, Irini

doi:10.1182/blood-2007-12-127878

Cited by 194 publications

(192 citation statements)

References 30 publications

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“…Indeed, by studying perturbations in cellular and molecular immune factors in human populations, it has been found that there is a segregation of factors necessary for control of systemic versus mucosal candidiasis. Specifically, it would appear that the adaptive immune response is most important for the development of effective host defense against mucosal infection, as patients with HIV and idiopathic CD4 lymphocytopenia are prone to mucocutaneous candidiasis but not systemic candidiasis (4,31). Furthermore, patients with either mutations in various components of the IL-17 pathway (i.e., IL-17RA, IL-17F, and ACT1 [14,32]) or with inherited immunodeficiencies that result in impaired IL-17 signaling (i.e., mutations in STAT1, STAT3, STK4, DOCK8, AIRE, and DECTIN-1 [11]) are susceptible to mucosal but not systemic candidiasis.…”

Section: Discussionmentioning

confidence: 99%

CX ₃ CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

et al. 2015

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g Candida albicans is part of the normal commensal microbiota of mucosal surfaces in a large percentage of the human population. However, perturbations of the host's immune response or bacterial microbiota have been shown to predispose individuals to the development of opportunistic Candida infections. It was recently discovered that a defect in the chemokine receptor CX 3 CR1 increases susceptibility of mice and humans to systemic candidiasis. However, whether CX 3 CR1 confers protection against mucosal C. albicans infection has not been investigated. Using two different mouse models, we found that Cx3cr1 is dispensable for the induction of interleukin 17A (IL-17A), IL-22, and IL-23 in the tongue after infection, as well as for the clearance of mucosal candidiasis from the tongue or lower gastrointestinal (GI) tract colonization. Furthermore, the dysfunctional human CX 3 CR1 allele CX 3 CR1-M280 was not associated with development of recurrent vulvovaginal candidiasis (RVVC) in women. Taken together, these data indicate that CX 3 CR1 is not essential for protection of the host against mucosal candidiasis, underscoring the dependence on different mammalian immune factors for control of mucosal versus systemic Candida infections. Candida albicans is a normal constituent of the human mucosal microbial ecology. However, inherited and acquired immunodeficiency syndromes and iatrogenic factors, such as catheter and antibiotic use, result in perturbations in the local mucosal immune environment and predispose patients to development of opportunistic mucosal Candida infections and systemic candidiasis due to translocation of yeast from mucosal surfaces into the systemic circulation (1, 2). The most common forms of mucosal candidiasis are oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC), while infections of the skin and nails occur less often (3). Although human mucosal candidiasis is not life threatening, it has a substantial global disease burden. For example, the majority of HIV-infected patients develop oral mucosal candidiasis (4), and approximately 75% of healthy reproductiveage women develop at least one episode of VVC during their lifetime. Furthermore, about 50% of these women develop at least one episode of recurrent infection, and 5 to 10% of them experience recurrent VVC (RVVC), defined as Ն3 episodes of infection per year (5). The substantial incidence and morbidity of mucosal candidiasis, the significant cost associated with it (i.e., the estimated annual cost of VVC exceeds $2 billion in the United States alone) (6), and the emerging resistance of Candida spp. to available antifungal agents that limits therapeutic options (7) highlight the importance of a better understanding of the cellular and molecular immune factors that mediate effective anti-Candida host defense at the mucosa and systemically, with an aim to develop immune-based strategies for risk stratification, prognostication, and/or treatment of affected patients.The chemokine receptor CX 3 CR1 binds specifically to its sole l...

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Section: Discussionmentioning

confidence: 99%

CX ₃ CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

et al. 2015

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“…The role of JCV-specific Abs in control of JCV infection is less clear because most PML patients show JCVspecific Abs before or at onset of the disease (22,23). The fact that PML occurs in situations of decreased CD4 + T cell numbers or compromised CD4 + cell functions (24)(25)(26) and often resolves after restoration of CD4 + numbers suggests that these T cells also play an important role in control of JCV. However, few studies have characterized JCV-specific CD4 + T cell responses in PML patients, most likely because these are reduced during PML and therefore difficult to examine.…”

Section: Irus-specific Cd4mentioning

confidence: 99%

TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

Yousef

Planas

Chakroun

et al. 2012

The Journal of Immunology

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Virus-specific CD4+ T cells play a central role in control of viral pathogens including JC polyoma virus (JCV) infection. JCV is a ubiquitous small DNA virus that leads to persistent infection of humans with no clinical consequences. However, under circumstances of immunocompromise, it is able to cause an opportunistic and often fatal infection of the brain called progressive multifocal leukoencephalopathy (PML). PML has emerged as a serious adverse event in multiple sclerosis patients treated with the anti–VLA-4 mAb natalizumab, which selectively inhibits cell migration across the blood–brain barrier and the gut’s vascular endothelium thus compromising immune surveillance in the CNS and gut. In a multiple sclerosis patient who developed PML under natalizumab treatment and a vigorous immune response against JCV after Ab washout, we had the unique opportunity to characterize in detail JCV-specific CD4+ T cell clones from the infected tissue during acute viral infection. The in-depth analysis of 14 brain-infiltrating, JCV-specific CD4+ T cell clones demonstrated that these cells use an unexpectedly broad spectrum of different strategies to mount an efficient JCV-specific immune response including TCR bias, HLA cross-restriction that increases avidity and influences in vivo expansion, and a combination of Th1 and Th1-2 functional phenotypes. The level of combinatorial diversity in TCR– and HLA–peptide interactions used by brain-infiltrating, JCV-specific CD4+ T cells has not, to our knowledge, been reported before in humans for other viral infections and confirms the exceptional plasticity that characterizes virus-specific immune responses.

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“…ICL is a rare and heterogeneous immunodeficiency of unknown aetiology 1. It was defined by the CDC in 1992 as ‘an absolute CD4-lymphocyte count of less than 0.3×10 9 /L or of less than 20% of total T cells, documented on more than one occasion, with negative HIV testing, and the absence of any immunodeficiency or therapy causing CD4 lymphopenia 2––4.…”

Section: Discussionmentioning

confidence: 99%

EBV-driven diffuse large B-cell lymphoma confined to the liver in a patient with a history of idiopathic CD4 lymphocytopenia

et al. 2013

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SUMMARYIdiopathic CD4 lymphocytopenia (ICL) is a rare immunodeficiency disorder. We describe a 49-year-old woman with a history of ICL who developed hepatic Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL). ICL was diagnosed at a time of her presentation with varicella-zoster virus (VZV) meningoencephalitis and chorioretinitis. Her CD4 count subsequently improved but remained at the lower limits of the normal range. Five years later she presented with cough, fever and night-sweat. She was found to have multiple liver nodules on MRI, fluorodeoxyglucose (FDG) avid on the positron emission tomography (PET) CT, histologically defined as DLBCL, EBV positive and of non-germinal centre type. To our knowledge this is the first reported case of EBV-positive DLBCL localised to the liver in the context of ICL. EBV-positive DLBCL typically occurs in immunocompromised individuals. The corticosteroid therapy she received for VZV meningoencephalitis may have contributed to the EBV reactivation with subsequent EBV-driven malignant transformation of B-cells. BACKGROUND

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Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors

Cited by 194 publications

References 30 publications

CX ₃ CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

CX ₃ CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

EBV-driven diffuse large B-cell lymphoma confined to the liver in a patient with a history of idiopathic CD4 lymphocytopenia

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Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors

Cited by 194 publications

References 30 publications

CX 3 CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

CX 3 CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection

EBV-driven diffuse large B-cell lymphoma confined to the liver in a patient with a history of idiopathic CD4 lymphocytopenia

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CX ₃ CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

CX ₃ CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans