Immunological profiles of immune restoration disease presenting as mycobacterial lymphadenitis and cryptococcal meningitis

Department of Clinical Immunology and Immunogenetics, Royal Perth Hospital, Australia
HIV Medicine (Impact Factor: 3.45). 04/2008; 9(5):307 - 316. DOI: 10.1111/j.1468-1293.2008.00565.x
Source: PubMed

ABSTRACT Objectives A proportion of HIV patients beginning antiretroviral therapy (ART) develop immune restoration disease (IRD). Immunological characteristics of IRD were investigated in a cohort of HIV patients beginning therapy in Kuala Lumpur, Malaysia.Methods Peripheral blood mononuclear cells were collected at weeks 0, 6, 12, 24 and 48 of ART from five patients experiencing IRD [two with cryptococcal and three with Mycobacterium tuberculosis (Mtb) disease], eight non-IRD controls who had begun ART with CD4 T-cell counts of <100 cells/μL and 17 healthy controls. Leukocytes producing interferon-gamma (IFNγ) were quantified by enzyme-linked immunospot assay after stimulation with purified protein derivative (PPD), early secretory antigenic target-6 (ESAT-6), Cryptococcus neoformans or Cytomegalovirus antigens. Plasma immunoglobulin (IgG) antibodies reactive with these antigens were assessed by enzyme-linked immunosorbent assay. Proportions of activated (HLA-DRhi) and regulatory (CD25 CD127lo and CTLA-4+) CD4 T-cells were quantified by flow cytometry.Results Plasma HIV RNA declined and CD4 T-cell counts rose within 8–27 weeks on ART. Mtb IRD patients displayed elevated IFNγ responses and/or plasma IgG to PPD, but none responded to ESAT-6. Cryptococcal IRD occurred in patients with low baseline CD4 T-cell counts and involved clear IFNγ and antibody responses to cryptococcal antigen. Proportions of activated and regulatory CD4 T-cells declined on ART, but remained higher in patients than in healthy controls. At the time of IRD, proportions of activated CD4 T-cells and regulatory CD4 T-cells were generally elevated relative to other patients.Conclusions Cryptococcal and Mtb IRD generally coincide with peaks in the proportion of activated T-cells, pathogen-specific IFNγ responses and reactive plasma IgG. IRD does not reflect a paucity of regulatory CD4 T-cells.

Download full-text


Available from: Dino Bee Aik Tan, Jul 29, 2015
  • Source
    • "Risk factors for IRIS include disseminated OI disease; recent OI treatment; low baseline CD4 with rapid rise after starting cART; and high baseline HIV VL with rapid decline after starting cART [14] [17] [20] [21]. Paradoxical IRIS in HIV-positive patients with previously treated cryptococcal disease has been estimated between 4 and 30% and is associated with an exaggerated T-cell mediated production of interferon-gamma to pathogen specific antigens [10] [12] [18] [22] [23]. The most common presentations of cryptococcal IRIS are either meningitis or lymphadenitis [24]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background. HIV-positive people starting combined antiretroviral therapy may develop immune reconstitution to latent or treated opportunistic infections. Immune reconstitution to cerebral Cryptococcus is poorly understood and can be fatal. Case Presentation. A 33-year-old Zimbabwean female presented with cryptococcal meningitis and newly diagnosed HIV with a CD4 count of 51 cells/μL (4%). She was treated with amphotericin and flucytosine. Combined antiretroviral therapy was started four weeks later and she showed early improvement. However, over the ensuing 18 months, her clinical course was marked by periodic worsening with symptoms resembling cryptococcal meningitis despite having achieved CD4 counts ≥400 cells/μL. Although initially treated for relapsing cryptococcal immune reconstitution syndrome, a brain biopsy taken 17 months after initial presentation showed budding Cryptococci. Conclusion. This unusually protracted case highlights the difficulties in differentiating relapsing cryptococcal meningitis from immune reconstitution and raises questions concerning the optimum timing of initiation of combined antiretroviral therapy in such patients.
    03/2014; 2014:164826. DOI:10.1155/2014/164826
  • Source
    • "Therefore, it is considered that Treg cells might be deficient in numbers or in function in IRIS patients. Instead Treg cells increased at the peak of IRIS symptoms [33]. In addition, a significant expansion of CD127 lo Foxp3 + CD25 + Treg cells was observed in IRIS patients compared with healthy controls and also compared with late-stage HIV-infected patients who commenced combination antiretroviral therapy without developing an IRIS [31]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pneumocystis pneumonia (PCP) occurs frequently in patients with immunodeficiency syndromes, especially AIDS. In order to investigate the role of IFN-gamma on PCP, nude mice deficient in IFN-gamma (GKO nude) and their wild-type ones (WT nude) were infected with murine Pneumocystis. Nine weeks later they were sacrificed, and cytokines in BALF and lung histopathology were compared between them. Cyst burden was greater in GKO than in WT nude mice. Histopathology in the lung was severer and granulomatous lesions were observed more frequently in GKO nude mice. Levels of IL-17 were higher in BALF of GKO than in that of WT nude mice. Greater number of CD4(+) T cells from lungs of infected GKO nude mice produced IL-17 than those from WT ones. These results suggest that deficiency in IFN-gamma induces the differentiation of Th17 and that IL-17 is responsible for inflammatory response in PCP.
    Immunology letters 10/2009; 127(1):55-9. DOI:10.1016/j.imlet.2009.08.013 · 2.37 Impact Factor
  • Source
    • "In contrast, in IRIS associated with fungi such as Cryptoccocus and Histoplasma (Lortholary et al., 2005a; Breton et al., 2006), protozoans such as Leishmania (Blanche et al., 2002), or mycobacteria, granulomatous inflammatory reactions can be triggered (Batista et al., 2008; Couppié et al., 2004; Philips et al., 2005). Furthermore, there is an increase in circulating Tcells that produce IFN-γ in patients with IRIS involving M. tuberculosis or Cryptococcus (Bourgarit et al., 2006; Tan et al., 2008). Suppuration of lymph nodes or other organs in mycobacterial IRIS (Philips et al., 2005; Burman et al., 2007; Puthanakit et al., 2005; Meintjes et al., 2008) is thought to be the result of the Th17 response, which is often mediated by neutrophils (Scriba et al., 2008; Matsuzaki et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV) restores immune responses against pathogens and has greatly decreased mortality. However, in about 25% to 35% of patients receiving HAART, the reconstituted immune system leads to a pathological inflammatory response, commonly known as immune reconstitution inflammatory syndrome (IRIS), which causes substantial short-term morbidity or even mortality. Although we have gleaned some knowledge on IRIS in the past few years, a number of unanswered questions remain. In this review, we discuss the definition, diagnostic criteria, pathogenesis, risk factors, clinical spectrum including oral manifestations, and management of IRIS.
    Oral Diseases 09/2009; 16(3):248-56. DOI:10.1111/j.1601-0825.2009.01628.x · 2.40 Impact Factor
Show more