Comment

Microbe exposure, innate immunity and autoimmunity

Experimental and epidemiological evidence suggests the benefit of exposure to microbial products (in the absence of infection, e.g., through vaccination) in multiple sclerosis (MS). In a pilot study, the bacillus Calmette-Guérin (BCG) vaccine was safe and effective in reducing disease activity as measured using magnetic resonance imaging (MRI), and in reducing the risk of developing persistent T1-hypointense lesions (“black holes,” an expression of tissue damage) in patients with MS. A placebo-controlled trial in people with clinically isolated syndrome (the onset, generally reversible, of MS) supported the findings of the pilot study. In that study, we observed a benefit on disease activity at MRI, a reduced risk of BH development, and a reduced risk of conversion to clinically definite MS over 5 years, during which time the patients took interferon beta starting six months after BCG or placebo. We suggest the use of BCG immediately after disease onset. Even the possible extension to people at risk of MS might be envisioned, being that the adjuvant approach is safe, cheap, and convenient.

Atopic diseases such as asthma, rhinitis, eczema and food allergies have increased in most industrialised countries of the world during the last 20 years. The reasons for this increase are not known and different hypotheses have been assessed including increased exposure to sensitising allergens or decreased stimulation of the immune system during critical periods of development.

In allergic diseases there is a polarisation of the Th2 response and an increase in the production of type 2 cytokines which are involved in the production of immunoglobulin E and the development of mast cells, basophils and eosinophils leading to inflammation and disease. The effector phase of atopy is initiated by interaction with FcεRI expressed on effector cells such as mast cells and basophils but also found on an ever increasing list of cells. Binding of a polyvalent allergen to the variable part of IgE leads to a cross-link of the receptor that triggers the cell to release histamine and pharmacological mediators of the symptomatic allergic response. Cross-linking of FcεRI by autoantibodies against the α-chain of the FcεRI, causing subsequent histamine release is thought to be involved in the pathogenesis of other diseases such as chronic idiopathic urticaria (CIU).

To date, most therapeutic strategies are aimed at inhibiting and controlling components of the inflammatory response. Recently, new treatment strategies have emerged that focus on the development of preventive and even curative treatments. The most promising therapeutic approaches are aimed at inhibiting the IgE–FcεRI interaction with the use of non-anaphylactogenic anti-IgE or anti-FcεRIα autoantibodies. Clinical trials in humans using an humanised anti-IgE antibody showed that this antibody was well tolerated and reduced both symptoms and use of medication in asthma and allergic rhinitis. Thus interruption of the atopic cascade at the level of the IgE–FcεRI interaction with the use of non-anaphylactogenic antibodies is effective and represents an attractive therapy for the treatment of atopic disease.

The immune response to helminth infections has long been known to share key features with the allergic response. In particular, both are typified by enhanced T helper 2 (Th2) responses with high levels of interleukin-4 (IL-4), IL-5 and IL-13, accompanied by eosinophilia and abundant IgE production. Paradoxically, the geographical distribution of helminth parasitism and allergic disease is complementary rather than coincident. Thus, the question arises does the Th2 response to parasites protect or pre-empt the host from developing Th2-linked allergic manifestations? It is suggested that downregulatory immune mechanisms, which dampen the anti-parasite response, might benefit the host by blocking progression to atopic reactions. This is of relevance in explaining how the ‘hygiene hypothesis’ might operate immunologically and in the design of therapeutics.

Increasing evidences show a global immune disregulation in multiple sclerosis (MS). The possible involvement of myelin and non-myelin (auto-)antigens in the autoaggressive process as well as the disregulation of both adaptive and innate immunity challenge the concept of specific immunotherapy. T cells at the boundary between innate and adaptive immunity, whose immunoregulatory role is becoming increasingly clear, have recently been shown to bear relevance for MS pathogenesis. Global immune interventions (and type I interferons may be considered as such) aimed at interfering with both innate and acquired immune responses seem to be a most promising therapeutic option in MS.

In animal models it is often possible to block Th1-mediated autoimmunity by deviating the response to Th2. In this article, Graham Rook and colleagues argue that this might prove a dangerous strategy in humans, and that we should distinguish between potentially pathogenic Th2 effector cells, and Th2-like physiological regulators of Th1 responses. The regulators might be triggered by appropriate Th1-inducing bacterial vaccines.

Studies on the in vivo effects of interferon-β (IFNβ) therapy on autoreactive T cells have never been carried out in multiple sclerosis (MS). We investigated the T cell response to myelin basic protein (MBP), before and after IFN-β therapy, raising MBP-specific T cell lines (TCL) from the peripheral blood of six MS patients with a satisfactory response to the treatment. IFNβ did not affect the relative frequency and epitope specificity of the TCL. After IFNβ therapy, the production of interleukin-4 was decreased in MBP-stimulated TCL while the secretion of interferon-γ was increased in unstimulated TCL. Interleukin-10 and tumor necrosis factor-α did not show significant variations. This finding supports recent suggestions about the complexity of the T helper 1/T helper 2 paradigm in MS and other organ-specific autoimmune diseases. In fact, the beneficial effects of IFNβ do not exclude an immunostimulatory action that may involve potentially autoreactive T cells. This has implications for future treatment options, including combination therapies.