Trained Immunity: A new concept of memory in Immunology

 Este post foi preparado pelo Dr. Joosten que é Pesquisador Visitante do Programa Ciência Sem Fronteira em Projeto coordenado pela Dra. Fátima Ribeiro-Dias da UFG. Ele está em Goiânia durante o mês de Julho e retornará ao Brasil duas vezes em 2015 e uma vez em 2016. Gostaria de agradecer ao Dr. Joosten pela sua contribuição para o crescimento da Imunologia em Goiânia e também por compartilhar um pouco de seu trabalho e de suas ideias com todos da SBI. Espero que apreciem.

Trained Immunity: A new concept of memory in Immunology

Very recently several articles were published that challenged the “dogma” that only the adaptive immunity is build on immunological memory. It reveals that also NK cells, monocytes and macrophages are able to build a kind of immunological memory. This concept of “Trained Immunity” may contribute to our understanding of several nonspecific effects seen within the field of immunology.

Immune responses in vertebrates are classically separated into innate or adaptive. Adaptive (or specific) immunity, requiring specialized cells such as T-lymphocytes and B-lymphocytes, specifically recognizes a pathogen and builds immunological memory to that specific. Upon a second encounter with the same pathogen, clonal expansion of memory T cells and/or B cells induces a rapid and effective response. In contrast to the adaptive immune responses, the current opinion holds that innate immune responses are nonspecific and lack immunological memory. Innate host defenses are mediated by cascades of constitutive proteins such as the complement system, and by cellular responses involving phagocytes (monocytes, macrophages, neutrophils) or natural killer (NK) cells.

The discovery of several major classes of pattern recognition receptors (PRRs), i.e., Toll-like receptors (TLRs), C-type lectin receptors, NOD-like receptors (NLRs), and RigI-helicases, implies that innate recognition of pathogens involves specific recognition of pathogen-associated molecular patterns (PAMPs). As a consequence, the innate response to different infectious agents may vary dependent on the type of PAMP-PRR interaction. The fact that innate immune responses exhibit memory characteristics after the first encounter with a pathogen (“training effect”) is accepted in plant immunology and is strongly suggested in invertebrates. The natural protection of plants against pathogens that spreads from the site of the infection throughout the tissues of the plant has been called “systemic acquired resistance” (SAR), a phenomenon documented already in 1933. Studies in invertebrates, which lacking T-cells and B-cells showed that invertebrates were protected against a secondary infection after they encounter a first not-related microorganism.  Several reports used mealworms, cockroaches, or fruit flies to show that invertebrates have both specific and non-specific protection to pathogens.

It is well known for long times that exposure to microorganisms or cytokines primed mice to enhanced immune responses in mice. In many experimental models for autoimmune diseases, like rheumatoid arthritis, it is known that heat killed Mycobacterium tuberculosis in Freund complete adjuvant is necessary for the development of the disease model. Interestingly, also protection was seen against models of infectious diseases. Previous exposure to low dose of Candida albicans or BCG protects against lethal infections caused by non-related pathogens. Of high interest, these protective effects were found in SCID mice, but in CCR2-deficient mice, indicated that monocytes and macrophages were the crucial cells in the phenomenon. In humans, BCG vaccinations revealed to protect against several other infectious diseases then tuberculosis alone. This so-called nonspecific protective effect of BCG is based on the activation state of monocytes and macrophages.  It was demonstrated that epigenetic modifications in monocytes that occurs after the first encounter with a microbe results in a long-lasting activation state of these monocytes. This epigenetic reprogramming of monocytes/macrophages reveals to be the mechanism of nonspecific protective effect of BCG in humans. The understanding of the mechanisms of “Trained Immunity” will lead to new insights for both vaccine development and the pathogenesis of several autoimmune diseases.

Dr. Leo A. B. Joosten, PhD
Department of Internal Medicine 
Radboud University Medical Centre 
Nijmegen, The Netherlands 
Leo.Joosten@radboudumc.nl

References:

Quintin J, et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe. 2012;12:223-32.

Kleinnijenhuis J, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012;109(43):17537-42.

Kleinnijenhuis J, et al. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responsesand innate trained immunity. J Innate Immun. 2014;6(2):152-8.

Levy O, et al. A prime time for trained immunity: innate immune memory in newborns and infants. Neonatology. 2014;105(2):136-41.

Quintin J, et al. Innate immune memory: towards a better understanding of host defense mechanisms. Curr Opin Immunol. 2014;29C:1-7

Bekkering S, et al. Oxidized Low-Density Lipoprotein Induces Long-Term Proinflammatory Cytokine Production and Foam Cell Formation via Epigenetic Reprogramming of Monocytes. Arterioscler Thromb Vasc Biol. 2014;34(8):1731-8.