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

Abstract

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. MethodsPeripheral 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 o100 cells/mL and 17 healthy controls. Leukocytes producing interferon-gamma (IFNg) were quantified by enzymelinked 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-DR hi ) and regulatory (CD25 CD127 lo and CTLA-4 1 ) CD4 T-cells were quantified by flow cytometry. ResultsPlasma HIV RNA declined and CD4 T-cell counts rose within 8-27 weeks on ART. Mtb IRD patients displayed elevated IFNg 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 IFNg 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. ConclusionsCryptococcal and Mtb IRD generally coincide with peaks in the proportion of activated T-cells, pathogen-specific IFNg responses and reactive plasma IgG. IRD does not reflect a paucity of regulatory CD4 T-cells.

Proliferation of weakly suppressive regulatory CD4+ T cells is associated with over‐active CD4+ T‐cell responses in HIV‐positive patients with mycobacterial immune restoration disease

“…Instead we found a significant expansion of CD127 lo Foxp3 + CD25 + Treg in IRD patients compared with healthy controls and also compared with late-stage HIV-infected patients who commenced cART without developing an IRD. This confirms the recently published observation that Treg are increased at the peak of IRD symptoms [26]. We reasoned that the high IL-2 levels produced in these patients might be involved in Treg survival and maintenance [39][40][41].…”

“…We show that effector CD4 + T cells specific for MAI antigen produce high levels of IFN-g and IL-2. We examined Treg frequency and found a significant expansion of CD127 lo Foxp3 + CD25 + Treg in IRD patients compared with controls, in agreement with a recent report [26]. However, when we performed in vitro suppression assays with these Treg we detected abnormalities in the function of both suppressor and responder cells in these patients.…”

“…Given that IRD results from an exaggerated host inflammatory response to antigens, Treg may play a central role in its immunopathogenesis. Recently, data from a prospective study showing elevated Treg proportions at the peak of IRD compared with controls have been reported [26]. In our study, using consecutive late-stage HIV-1-infected patients who developed mycobacterial IRD, we reasoned that Treg could be defective in either numbers and/or function and therefore be unable to ensure the physiological equilibrium of the immune system in patients with IRD.…”

Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

“…Two forms of TB-IRIS have been described, namely paradoxical and unmasking. Whereas the paradoxical form manifests as new or recurrent TB disease in subjects with treated TB during early cART, the unmasking form mainly results from an exaggerated, nonclassical inflammatory presentation of TB during early cART (5)(6)(7)(8)(9).…”

L’iris

“…Ainsi, les réponses à la tuberculine, composée d'un extrait complexe de protéines purifiées dérivées de Mtb, sont fortement augmentées durant le TB-IRIS. En revanche, les réponses dirigées contre d'autres antigènes dérivés de Mtb, tels que ESAT-6 (6-kDa early secreted antigenic target from Mtb), CFP-10 (Mtb secretory protein-10) et TB7.7, ne sont pas augmentées dans les formes paradoxales de TB-IRIS, alors qu'elles peuvent l'être dans les formes démasquées [24][25][26]. Ces différences reflètent, sans doute, le fait que la réponse du TB-IRIS paradoxal est dirigée contre des mycobactéries mortes, car tuées par le traitement antituberculeux, alors que les réponses du TB-IRIS démasqué sont dirigées contre les mycobactéries vivantes.…”