Leprosy as a Model of Immunity

Yang Degang; Kazuaki Nakamura; Takeshi Akama; Yuko Ishido; Yuqian Luo; Norihisa Ishii; Koichi Suzuki

Disclosures

Future Microbiol. 2014;9(1):43-54. 

In This Article

Type II Lepra Reaction (Erythema Nodosum Leprosum): Signs of a M. leprae-Specific Cellular Immune Response?

In contrast to a type I reaction, type II occurs more often in the patients around the LL pole of the leprosy spectrum with a heavy load of bacilli. Type II reactions affect 20% of LL and 10% of BL cases, in which a high bacterial load and diffuse infiltration in skin lesions are regarded as important risk factors.[9,19] Logistic regression analysis identified LL and BL with a bacterial index of more than four as major risk factors.[25] A type II reaction is characterized by painful and tender red papules or nodules on the skin, the typical signs of erythema nodosum (i.e., why type II also refers to erythema nodosum leprosum), accompanied by systemic symptoms including fever, joint pain, edema, proteinuria and malaise.[9,19] Neuritis may also be part of the type II reaction; however, it is usually milder compared with type I reactions.[26] Type II reactions may occur in the early stages of the treatment, however, the majority of the cases present 2–3 years after leprosy diagnosis, while some patients developed episodes as late as 7 years after starting treatment.[27] Most patients experience multiple acute episodes or a chronic type II reaction lasting more than 6 months or even years.[28] In fact, 65% of cases had multiple episodes of type II reaction, requiring management with long courses of prednisolone and additional clofazimine for periods of up to 5 years.[27] These data indicate that the body needs a long time to get rid of a heavy load of even dead bacilli within the macrophages.

The inflammatory infiltrate is usually seen in the deeper layers of the dermis and subcutis.[26] In acute lesions, within 72 h polymorphonuclear leukocytes are the predominant cell type, whereas between 72–96 h equal numbers of neutrophils, lymphocytes and plasma cells are seen, along with the presence of mast cells.[26] Chronic lesions show fewer neutrophils and eosinophils, but increased numbers of lymphocytes.[26] Vasculitis appears to be a major pathological event in type II reactions, along with interstitial edema, and degenerative and necrotizing changes seen in classical vasculitis.[29,30] Type II reactions have been found to be associated with deposition of immune complexes in circulation and multiple tissues (skin, eyes, joints, lymph nodes, kidneys, liver, spleen, bone marrow, endothelium and testes), indicating the involvement of activated humoral immunity in type II reactions. In one study, a large proportion of patients with type II reactions demonstrated deposition of immunoglobulin and complement in the skin, with 70% presented M. leprae antigens within the complexes, which were absent in patients without type II reactions.[31]

A M. leprae-specific cellular immune response is absent in LL patients, which has been shown by the lack of delayed type hypersensitivity, as evidenced by negative results from the lepromin test.[10–12] Reactivation of the cellular immune responses in BL/LL patients with type II reactions was later demonstrated by a strong inhibition of leukocyte migration and antigen-induced lymph proliferation in peripheral blood mononuclear cells (PBMCs).[32] Thus, generalized activation of the cellular immune response may also be a crucial component of type II reactions.[33–36] IFN-γ, one of the key components of an activated cellular immune response, was detected in PBMCs not only from patients with type I reactions, but also from 84.6% of patients with type II reactions.[37] Neopterin is mainly derived from GTP due to the activity of GTP cyclohydrolase I coupled with a relative deficiency of 6-pyruvoyl tetrahydropterin synthase in macrophages.[38] IFN-γ is the central stimulus for GTP cyclohydrolase I-mediated production of neopterin. The presence of neopterin in body fluids may be further evidence for the activation of the cellular immune response.[38] Elevated levels of serum neopterin were reported in 75% of leprosy patients, including lepromatous (LL/BL) patients, particularly those with lepra reactions (compared with healthy controls or nonreactional leprosy patients),[39–41] suggesting activation of cellular immune responses in BL/LL patients, especially those with type II reactions.

The management of severe type II reactions is often difficult and controversial; for example, the dosage of corticosteroids is limited and the mechanism of action of clofazimine is unclear. Thus, whether these two major drugs affect M. leprae viability remains a question according to the 'WHO Guidelines for the management of severe erythema nodosum leprosum reactions'. Thalidomide is an effective treatment for type II reactions and its effectiveness is mainly attributed to the inhibition of TNF.[42] Many thalidomide trials have confirmed its usefulness in controlling type II lepra reactions;[43] however, it provides no benefit in type I reactions. Thalidomide has been chosen for the management of type II reactions mainly owing to its speed of action (effective in 24 h in most cases) as well as its ability to spare the use of steroids.[44] However, WHO does not support the use of thalidomide in the management of type II reaction in leprosy owing to the teratogenic side effects of the drug at present. Since TNF-α is crucial in host defenses against intracellular pathogens, and anti-TNF-α antibodies have been shown to suppress cellular immunity in vivo,[45,46] these antibodies may also be effective in treating type II reaction. Therefore, neutralization of TNF-α with monoclonal antibodies or soluble inhibitors, as used in rheumatoid arthritis and Crohn's disease, may be a candidate for new type II reaction treatment. Such a possibility has been previously discussed,[47,48] but needs to be assessed in controlled clinical studies. However, the potential risk for deterioration of the disease by suppressing immunity should never be neglected.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....