Sarcoidosis and Immune Reconstitution

Acute sarcoidosis (Loefgren’s syndrome) and immune reconstitution

Volker Nehls

Acute sarcoidosis typically appears as swollen ankle joints, erythema nodosum and hilar lymphadenopathy. The etiology remains enigmatic, but most clinicians believe that diverse antigens presented by macrophages and dendritic cells to T-lymphocytes are capable of triggering an Th1-oriented immune reaction finally leading to granuloma formation.

There is constant surveillance of all tissues by immune cells, and the question arises of how sudden appearance of inflammatory symptoms can be explained although some provoking antigens are permanently present in the body. It is tempting to speculate thus that immune functions are suppressed by unknown factors prior to outbreak of sarcoidosis symptoms.

Recovery of the immune system during antiretroviral treatment of HIV-infected patients frequently leads to immune reconstitution inflammatory syndrome (IRIS, Dhasmana et al., 2008). IRIS exhibits very heterogenous phenotypes among which cases of sarcoidosis were also described (Shiohara et al., 2010). In general, IRIS is defined as paradoxical deterioration of clinical conditions attributable to restoration of the immune response. IRIS is not confined to HIV-infected patients, but occurs also when immunosuppressive drugs are reduced, e.g. corticosteroid withdrawal syndrome (Shiohara et al., 2010).

Statistically, depression and major stress events precede sarcoidosis onset, and individuals living under precarious socioeconomic conditions bear increased risk to become afflicted with the disease (Yamada et al., 2003, Rabin et al., 2004; Goracci et al., 2008). Psychosocial stress leads to activation of the hypothalamic-pituitary-adrenal axis and release of cortisol from the adrenal glands.

Cortisol potently suppresses antigen-presentation by macrophages and dendritic cells and, additionally, the Th1-differentiation of T-lymphocytes (Franchimont et al., 2000). Further, the generation of tolerogenic dendritic cells which downregulate IL-12 is strongly promoted by glucocorticoids (Adler and Steinbrink, 2007).

When major stress events activate the hypothalamus-pituitary-adrenal axis, increased cortisol results in depressed cellular immunity. During recovery from stress, declining cortisol levels might result in abrupt reconvalescence and rapid growth of granulomatous tissue in susceptible patients. In support of this hypothesis, cases of sarcoidosis were described in patients after successful treatment of Cushing’s syndrome (Schaefer et al., 2010).

Hence, sarcoid immune reactions partially could result from changing cortisol concentrations and/or reduced sensitivity of the glucocorticoid receptor. Individuals reared under harsh psychosocial conditions apparently develop desensitization of the glucocorticoid receptor, with increased stimulated IL-6 secretion by monocytes (Miller et al., 2005-2010). It appears tempting to speculate thus that proinflammatory imprinting of the glucocorticoid signaling system might lead to enhanced vulnerability for granulomatous disease. However, it remains to be shown whether desensitization of the glucocorticoid receptor actually can be demonstrated in sarcoidosis patients.

Apart from alterations in corticosteroid sensitivity, recovery syndromes could also be induced by viral infections other than HIV. Human herpesvirus-6, for example, persists in a latent state in almost all adults and preferably in CD4(+) - T-lymphocytes. Reactivation of the virus may result in a mononucleosis-like disease with lymphadenitis, fever and fatigue (Maric et al., 2004), and, further, reactivation of the virus has been linked with drug-induced hypersensitivity syndrome (Shiohara et al., 2010).

HHV-6 infected T-lymphocytes show profound immunological changes, including decreased ability to become stimulated by antigen-presenting cells selective downregulation of IL-12 expression, and increase of the immunosuppressive cytokine IL-10 (Ablashi et al., 1988; Lusso et al., 2006; Otani und Okuno, 2007; Smith et al., 2003; Sullivan und Coscoy, 2008). In general, reactivation of HHV-6 leads to a shifting of the immune response from Th1- to Th2-orientation.

It appears conceivable therefore that recovery from HHV-6 infection might result in overshooting Th1-oriented “cellular” inflammation. Although evidence supporting this hypothesis is lacking so far, reactivation of HHV-6 was shown in other lymphoproliferative diseases and also in individuals afflicted with sarcoidosis (Biberfeld et al., 1988; Ablashi et al., 1988).

In conclusion, immune reconstitution inflammatory syndromes may arise during recovery from drug-induced or virus-induced immunosuppression. Among a multitude of phenotypes, sarcoidosis is only one clinical manifestation of IRIS. It remains to be seen whether dysregulated and exaggerated immune recovery is a principal etiologic factor in the pathogenesis of acute sarcoidosis.

online since Jan 02, 2012



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