T CELLS
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Key messages
T cells
variability and, thus, an extend- ed repertoire of TCRs that cover most determinants of our environ- ment is generated. Apart from the sophisticated structure of TCRs, the activation and differentiation of these cells is integrating mul- tiple signals from the tissue, the immune system and the external environment. This integration pro- cess involves antigen-presenting cells (APC) that need to digest the environmental allergen/antigen and present it in a molecule with similar high diversity as the TCR. Major histocompatibility com- plexes, (MHC) bring the digested peptides to the surface of the APC and also deliver additional signals that are essential for the activa- tion or deactivation of T cells. The successful activated T cell will di- vide and after the termination of an immune response some cells (memory cells) will remain. These
memory cells are able to quickly expand and reproduce an immune response that has been proven to be successful. It is anticipated that the generation of memory cells is underlying successful immuniza- tions (vaccination) against infec- tious agents. Hyposensitisation by allergen-specific immunother- apy (AIT) may also be governed by memory populations.
DECISION MAKING IN THE IMMUNE SYSTEM
The decision making process is subject of immunology research and has the intention to solve the “black box” of immune tolerance mechanisms. The goals are to prevent the loss of immune tol- erance by means of public health initiatives (e.g. pollution control, dietary advices etc.), to increase effectiveness of specific immuno- therapy and similar vaccination
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strategies and to develop new therapies that prevent severe tis- sue damage as it occurs in the gut, skin and airways. The decision of the immune system is reflected by the T lymphocyte activity, mainly by their secreted mediators, in- terleukins (IL). Interleukins are typically of the “Th2”-type includ- ing IL-4, IL-5 and IL-13, whereas autoimmune or pathogen-trigged T cells usually express “Th1- or Th17-type” IL’s and interferons (IFN) such as IFN-γ or IL-17. IL-4 produced by T cells is essential for the production of IgE, the diagnos- tic key parameter in the detection of allergies. The interleukins have various functions and are charac- terizing the regulatory impact of T cells on other immune cells and on tissue cells. The exploration of T cell mediated signals on tis- sue cells is just beginning and it is already revealed that T cells can directly mediate tissue pathology such as epithelial damage or colla- gen deposition (Figure 1).
TERMINATING IMMUNE RESPONSES
This holds particularly true for the immune system. T regulatory (Treg) cells represent a key discov- ery that falls into this category, as they are actively suppressing oth- er immune cells particularly Th1, -2 and-17 cells. In fact, healthy individuals are showing immune activation in vitro, suggesting that mechanisms exist that keep these processes under asymptomatic control. Novel immune regulato- ry T cell phenotypes are hypothe- sized to mediate anti-inflammato- ry signals also to tissue cells. AIT is assumed to generate Treg cells and future research and novel phar- maceutical strategies are aiming to reinforce these mechanisms in order to re-construct immune tol- erance under minimal influence on anti-pathogen responses.
KEY REFERENCES
1. Schmidt-Weber CB, Akdis M, Akdis CA. TH17 cells in the big picture of
immunology. J Allergy Clin Immunol 2007;120:247-254.
2. Stott B, Lavender P, Lehmann S, Pennino D, Durham S, Schmidt-We- ber CB. Human IL-31 is induced by IL-4 and promotes TH2-driven in- flammation. J Allergy Clin Immunol 2013;132:446-54 e5.
3. Eyerich S, Onken AT, Weidinger S, Franke A, Nasorri F, Pennino D, et al. Mutual antagonism of T cells causing psoriasis and atopic ecze- ma. N Engl J Med 2011;365:231- 238.
4. Akdis M, Verhagen J, Taylor A, Kar- amloo F, Karagiannidis C, Crameri R, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance be- tween allergen-specific T regulato- ry 1 and T helper 2 cells. J Exp Med 2004;199:1567-1575.
5. Pennino D, Bhavsar PK, Effner R, Avitabile S, Venn P, Quaranta M, et al. IL-22 suppresses IFN-gam- ma-mediated lung inflammation in asthmatic patients. J Allergy Clin
Immunol 2013;131:562-570.
Figure 1 Different T cell phenotypes arise from naïve (resting, not antigen-experienced T cells) upon activation by antigen-presenting cells and by decision cytokines (not shown). The figure highlights a variety of responding cells both of
the immune system as well as from non-immune (mesenteric) origin.
T cells spec. immunity spongiosis shedding remodeling, unspec. immunity inhibition of MHC I & II bronchiale hypersensitivity airway - "remodelling"
itch immediate type reactions anti- microbial tissue
homeostatis
acute inflammation
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• By their production of allergen-specific IgE antibodies B cells contribute to the pathophysiology of a wide range of allergic diseases
• CD4+ Th2 cells that produce IL-4 and express CD40L orchestrate
the IgE-switch and differentiation of B cells
• The recently described B regulatory cells inhibit over-activated immune responses
• Elucidating mechanisms regulating the bifurcation of B cell responses into B regulatory versus IgE-producing cells holds promise for therapeutic interventions
B cells are crucial in allergic dis- eases by virtue of their production of allergen-specific IgE antibodies, which play a key role in instigat- ing immediate hypersensitivity reactions and contribute to the pathophysiology of a wide range of allergic diseases ranging from asthma, atopic dermatitis, food and drug allergy, amongst others. IgE-production by B cells entails class-switch recombination at the immunoglobulin heavy chain locus into the IgE heavy chain (Cε). CD4+
Th2 cells that produce IL-4 and express CD40L orchestrate the differentiation of IgE-switched B cells. It has been suggested that there are two pathways for IgE production after secondary expo- sure to antigen.
The first involves the differen- tiation of IgE-switched plasma cells from IgG1+ precursors by
sequential switching from Cγ1 to Cε, leading to the production of high affinity IgE antibodies by somatic hypermutation (affinity maturation). The second pathway involves the direct differentiation of IgE+ memory B cells generated
during the primary immune re- sponse into plasma cells, leading to a robust recall IgE antibody re- sponse. The relative contribution
B CELLS
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Key messages
B cells
of each pathway to the generation of disease-promoting pathogenic IgE antibodies remains to be es- tablished (Figure 1).
The highly variable correlation be- tween the levels of allergen-spe- cific IgE antibodies and suscepti- bility to anaphylaxis indicates that other factors, such as IgG antibod- ies, have profound influences on IgE-mediated responses. Immuno- therapy to aeroallergens has been shown to stimulate the production of allergen-specific IgG1 and IgG4 antibodies, that protect against disease by inhibiting allergen in- teraction with FcεRI-bound IgE on mast cells and basophils, thus pre- venting their degranulation. Recently, much attention has been
given to regulatory B (Breg) cells that inhibit over-activated im- mune responses. Several groups have proposed that a reduction in Breg cells worsens symptoms of allergic disease such as contact hypersensitivity and anaphylax- is. Breg cells are characterized by their production of the negative regulatory cytokines, IL-10 and TGF-β. An increased number of IL-10-producing B cells has been found in S. mansoni worm infection and the in vivo transfer of these cells prevents recipient mice from anaphylaxis. Breg cells proliferate when stimulated with the milk an- tigen casein in milk tolerant but not in milk allergic patients. Akdis and colleagues recently found in- creased suppressive IL10+ Breg