Resumen de Immune response in human neurological and allergic diseases
Summary Infectious diseases are an increasing problem worldwide and the development of pathological immune responses after suffering an infection, as autoimmune responses or hypersensitivity reactions, constitute a serious threat to the population.
The present thesis is focused on the characterization, by omics approaches, of the immune responses generated in two immune-related diseases with a growing incidence worldwide: The Guillain-Barré syndrome (GBS) and the -Gal syndrome (AGS) with the aim of identify possible target molecules for diagnostics, treatment and prevention of these diseases.
Chapter I: Guillain-Barré syndrome Chapter Ia. This chapter contains a review paper that constitutes an introduction about the relevance of GBS and the application of post-genomics technologies approaches to characterize this disease. GBS is an autoimmune-mediated peripheral neuropathy identified as the main cause of the acute neuromuscular paralysis worldwide. This review summarizes the main findings obtained after the application of omics technologies to the study of GBS and the possibilities that offer for the characterization of the biological mechanisms involved in the pathogenesis, the discovery of new biomarkers for diagnosis and monitoring, and the development of novel therapeutic strategies for this disease. (Villar M, Mateos-Hernández L, de la Fuente J. The impact of post-genomics approaches in neurodegenerative demyelinating diseases: the case of Guillain-Barré syndrome).
Chapter Ib. In this chapter, the transcriptome from a GBS patient is compared with the transcriptomes of her healthy twin, spinal cord injury (SCI) unrelated patients with similar medications and healthy individuals with the aim to discover possible biomarkers of disease progression and recovery. Results show the first evidence for the implication of the Early Growth Response Gen-2 (EGR2) during disease recovery. EGR2 overexpression in GBS patients resulted in downregulation of several cytokines (IL-17, IL-22, IL-28A, and TNF-β) implicated in GBS pathophysiology, providing a candidate biomarker to study disease progression. (Doncel-Pérez E, Mateos-Hernández L, Pareja E, García-Forcada Á, Villar M, Tobes R, Romero Ganuza F, Vila Del Sol V, Ramos R, Fernández de Mera IG, de la Fuente J. Expression of Early Growth Response Gene-2 and Regulated Cytokines Correlates with Recovery from Guillain-Barré Syndrome. J Immunol. 2016; 196(3): 1102-7). doi: 10.1016/j.pt.2015.06.016).
Chapter Ic. This chapter is a complementary study to chapter Ib. In this case, a quantitative proteomics approach using isobaric tags for relative and absolute quantitation (iTRAQ) labeling was used to characterize differences in the serum proteome of the same individuals analyzed in chapter Ib. Serum samples represent an attractive alternative to cerebrospinal fluid because it is easier to obtain and has potential for biomarkers discovery. The results show that Piccolo, a protein essential in the maintenance of presynaptic active zone structure, was over-represented in GBS patients recovering from the acute disease phase. Proteomics results were corroborated by ELISA analysis of serum samples, and a negative correlation was obtained between Piccolo serum levels and patient functional status, noticing an increase in Piccolo serum levels during disease recovery. These results provided the first evidence of the Piccolo´s putative role in GBS, suggesting a candidate target for developing a serological marker for disease recovery. (Mateos-Hernández L, Villar M, Doncel-Pérez E, Trevisan-Herraz M, García-Forcada A, Ganuza FR, Vázquez J, de la Fuente J. Quantitative proteomics reveals Piccolo as a candidate serological correlate of recovery from Guillain-Barré syndrome. Oncotarget. 2016; 7(46): 74582-74591). doi: 10.18632/oncotarget.15243) Chapter II: The -Gal syndrome Chapter IIa. This chapter contains a review paper introducing the relationship about vector-borne diseases and the immune response to the carbohydrate -Gal (Galα1-3Galβ1-(3)4GlcNAc-R). Arthropod vectors have been involved in emerging anaphylactic diseases. In particular, the immunoglobulin E (IgE) antibody response to -Gal following a tick bite has been associated with allergies to red meat, cetuximab, and gelatin. By contrast, an anti-a-gal IgM antibody response has been shown to protect against mosquito-borne malaria. In this review, the interplay between the gut microbiota, vectors, transmitted pathogens, and the regulation of the immune response was studied as a model to understand the protective or allergic effect -Gal. Establishing the source of -Gal in arthropod vectors and the immune response to vector bites and transmitted pathogens will be essential for diagnosing, treating, and ultimately preventing these emerging anaphylactic and other vector-borne diseases. (Cabezas-Cruz A, Mateos-Hernández L, Pérez-Cruz M, Valdés JJ, Mera IG, Villar M, de la Fuente J. Regulation of the Immune Response to α-Gal and Vector-borne Diseases. Trends Parasitol. 2015; 31(10): 470-6. doi: 10.1016/j.pt.2015.06.016).
Chapter IIb. In this chapter, to expand our knowledge of -Gal syndrome and characterize the proteins associated with anaphylaxis to tick bite, a comparative proteomics approach was applied in patients with red meat tolerance, but with different degrees of hypersensitivity to tick bite. The results support a patient specific IgE antibody response to tick species responsible for the anaphylaxis to tick bite. Patients and healthy individual, serologically recognized tick proteins with and without α-Gal modifications, with proteins differentially recognized by patients but not control sera. These proteins could be used as potential antigens for diagnostics, treatment and prevention of tick bite-induced allergies. (Mateos-Hernández L, Villar M, Moral A, Rodríguez CG, Arias TA, de la Osa V, Brito FF, Fernández de Mera IG, Alberdi P, Ruiz-Fons F, Cabezas-Cruz A, Estrada-Peña A, de la Fuente J. Tick-host conflict: immunoglobulin E antibodies to tick proteins in patients with anaphylaxis to tick bite. Oncotarget. 2017; 8(13): 20630-20644. doi: 10.18632/oncotarget.15243).
Chapter IIc. This chapter describes an attempt to identify factors affecting the susceptibility to infectious diseases. In this case, due to the facts that the ABO blood group correlates with susceptibility to malaria and other infectious diseases and the structural similarity between blood antigen B and -Gal, the correlation between the frequency of blood type B and the incidence of infectious diseases was analyzed. It has been found a positive correlation between the frequency of blood type B in endemic regions and the incidence of malaria and tuberculosis, caused by pathogens with -Gal on their surface whereas no correlation was found with the incidence of dengue fever, caused by a pathogen without -Gal. Furthermore, the incidence of malaria and tuberculosis was negatively correlated with the anti-α-Gal antibody protective response. Thereby, it seems that self-tolerance to antigen B affects the immune response to α-Gal, which in turn affects the susceptibility to infectious diseases caused by pathogens carrying α-Gal on their surface, whith has important implications for disease control and prevention. (Cabezas-Cruz A, Mateos-Hernández L, Alberdi P, Villar M, Riveau G, Hermann E, Schacht AM, Khalife J, Correia-Neves M, Gortazar C, de la Fuente J. Effect of blood type on anti-α-Gal immunity and the incidence of infectious diseases. Exp Mol Med. 2017; 49(3): e301. doi: 10.1038/emm.2016.164.) Chapter IId. This chapter summarizes the possible immunological basis of tick-induced allergy to red meat and the role of salivary prostaglandin E2 (PGE2) on it. PGE2 could induce class switch recombination (CSR) towards IgE production on pre-existing anti-α-Gal IgM-and / or IgG-specific mature B cell clones, and blood type B-negative individuals will be more susceptible to develop α-Gal-related allergy to red meat after tick bites. The data currently available seem to suggest that there are three main risk factors for developing tick-induced allergy to red meat: (i) the presence of a-Gal-producing bacteria within the gut microbiota, (ii) the absence of blood type B, and (iii) the exposition to tick salivary PGE2 after tick bites. (Cabezas-Cruz A, Mateos-Hernández L, Chmelař JC, Villar M, de la Fuente J Salivary Prostaglandin E2: Role in Tick-Induced Allergy to Red Meat. Trends Parasitol. 2017; 33(7): 495-498. doi: 10.1016/j.pt.2017.03.004).
Chapter III: General discussion: Guillain-Barré and α-Gal syndromes: What put them together? In the last chapter, a general discussion about the Guillain-Barré syndrome and the -Gal syndrome is presented. GBS and AGS are related to infectious diseases and driven by immune response to galactose-containing oligosaccharide structures and the immunological basis of both syndromes are similar. Trying to understand how immunity is regulated in response to galactose-containing oligosaccharide structures produced by pathogens and ticks that result in GBS or AGS is essential to prevent these diseases. The application of latest post-genomic or omics technologies would facilitate the characterization of the immune response in GBS and AGS with the possible identification of target molecules for diagnostics, treatment and prevention of these diseases. (de la Fuente J, Mateos-Hernandez L, Villar M, Cabezas-Cruz a. Guillain-Barré and α-Gal syndromes: What put them together? Submitted)
