Targeting DEC-205-DCIR2+ dendritic cells promotes immunological tolerance in proteolipid protein-induced experimental autoimmune encephalomyelitis.

BACKGROUND: Dendritic cells (DC) induce adaptive responses against foreign antigens, and play an essential role in maintaining peripheral tolerance to self-antigens. Therefore they are involved in preventing fatal autoimmunity. Selective delivery of antigens to immature DC via the endocytic DEC-205 receptor on their surface promotes antigen-specific T cell tolerance, both by recessive and dominant mechanisms. We provide evidence that the induction of antigen-specific T cell tolerance is not a unique property of CD11c+CD8+DEC-205+ DCs. METHODS: We employed a fusion between αDCIR2 antibodies and the highly encephalitogenic peptide 139-151 of myelin-derived proteolipid protein (PLP139-151), to target CD11c +CD8- DCs with a DEC-205-DCIR2+ phenotype in vivo, and to substantially improve clinical symptoms in the PLP139-151-induced model of experimental autoimmune encephalomyelitis (EAE). RESULTS: Consistent with previous studies targeting other cell surface receptors, EAE protection mediated by αDCIR2-PLP139-151 fusion antibody (Ab) depended on an immature state of targeted DCIR2+ DCs. The mechanism of αDCIR2-PLP139-151 mAb function included the deletion of IL-17- and IFN-γ-producing pathogenic T cells, as well as the enhancement of regulatory T (Treg) cell activity. In contrast to the effect of αDEC-205+ fusion antibodies, which involves extrathymic induction of a Foxp3+ Treg cell phenotype in naïve CD4+Foxp3- T cells, treatment of animals with DCIR2+ fusion antibodies resulted in antigen-specific activation and proliferative expansion of natural Foxp3+ Treg cells. CONCLUSIONS: These results suggest that multiple mechanisms can lead to the expansion of the Treg population, depending on the DC subset and receptor targeted.

Dominant sequences of human major histocompatibility complex conserved extended haplotypes from HLA-DQA2 to DAXX.

We resequenced and phased 27 kb of DNA within 580 kb of the MHC class II region in 158 population chromosomes, most of which were conserved extended haplotypes (CEHs) of European descent or contained their centromeric fragments. We determined the single nucleotide polymorphism and deletion-insertion polymorphism alleles of the dominant sequences from HLA-DQA2 to DAXX for these CEHs. Nine of 13 CEHs remained sufficiently intact to possess a dominant sequence extending at least to DAXX, 230 kb centromeric to HLA-DPB1. We identified the regions centromeric to HLA-DQB1 within which single instances of eight "common" European MHC haplotypes previously sequenced by the MHC Haplotype Project (MHP) were representative of those dominant CEH sequences. Only two MHP haplotypes had a dominant CEH sequence throughout the centromeric and extended class II region and one MHP haplotype did not represent a known European CEH anywhere in the region. We identified the centromeric recombination transition points of other MHP sequences from CEH representation to non-representation. Several CEH pairs or groups shared sequence identity in small blocks but had significantly different (although still conserved for each separate CEH) sequences in surrounding regions. These patterns partly explain strong calculated linkage disequilibrium over only short (tens to hundreds of kilobases) distances in the context of a finite number of observed megabase-length CEHs comprising half a population's haplotypes. Our results provide a clearer picture of European CEH class II allelic structure and population haplotype architecture, improved regional CEH markers, and raise questions concerning regional recombination hotspots.

Variants in toll-like receptor 9 gene influence susceptibility to tuberculosis in a Mexican population.

BACKGROUND: The control of Mycobacterium tuberculosis (Mtb) infection begins with the recognition of mycobacterial structural components by toll like receptors (TLRs) and other pattern recognition receptors. Our objective was to determine the influence of TLRs polymorphisms in the susceptibility to develop tuberculosis (TB) in Amerindian individuals from a rural area of Oaxaca, Mexico with high TB incidence. METHODS: We carried out a case-control association community based study, genotyping 12 polymorphisms of TLR2, TLR4, TLR6 and TLR9 genes in 90 patients with confirmed pulmonary TB and 90 unrelated exposed but asymptomatic household contacts. RESULTS: We found a significant increase in the frequency of the allele A of the TLR9 gene polymorphism rs352139 (A>G) in the group of TB patients (g.f. = 0.522) when compared with controls (g.f. = 0.383), (Pcorr = 0.01, OR = 1.75). Under the recessive model (A/G + A/A vs G/G) this polymorphism was also significantly associated with TB (Pcorr = 0.01, OR= 2.37). The association of the SNP rs352139 was statistically significant after adjustment by age, gender and comorbidities by regression logistic analysis (Dominant model: p value = 0.016, OR = 2.31; Additive model: p value = 0.023, OR = 1.68). The haplotype GAA of TLR9 SNPs was also associated with TB susceptibility (Pcorr = 0.02). Differences in the genotype or allele frequencies of TLR2, TLR4 and TLR6 polymorphisms between TB patients and healthy contacts were not detected. CONCLUSIONS: Our study suggests that the allele A of the intronic polymorphism rs352139 on TLR9 gene might contribute to the risk of developing TB in Mexican Amerindians.

MHC Class II haplotypes of Colombian Amerindian tribes.

We analyzed 1041 individuals belonging to 17 Amerindian tribes of Colombia, Chimila, Bari and Tunebo (Chibcha linguistic family), Embera, Waunana (Choco linguistic family), Puinave and Nukak (Maku-Puinave linguistic families), Cubeo, Guanano, Tucano, Desano and Piratapuyo (Tukano linguistic family), Guahibo and Guayabero (Guayabero Linguistic Family), Curripaco and Piapoco (Arawak linguistic family) and Yucpa (Karib linguistic family). for MHC class II haplotypes (HLA-DRB1, DQA1, DQB1). Approximately 90% of the MHC class II haplotypes found among these tribes are haplotypes frequently encountered in other Amerindian tribes. Nonetheless, striking differences were observed among Chibcha and non-Chibcha speaking tribes. The DRB1*04:04, DRB1*04:11, DRB1*09:01 carrying haplotypes were frequently found among non-Chibcha speaking tribes, while the DRB1*04:07 haplotype showed significant frequencies among Chibcha speaking tribes, and only marginal frequencies among non-Chibcha speaking tribes. Our results suggest that the differences in MHC class II haplotype frequency found among Chibcha and non-Chibcha speaking tribes could be due to genetic differentiation in Mesoamerica of the ancestral Amerindian population into Chibcha and non-Chibcha speaking populations before they entered into South America.

Cellular and humoral mechanisms involved in the control of tuberculosis.

Mycobacterium tuberculosis (Mtb) infection is a major international public health problem. One-third of the world's population is thought to have latent tuberculosis, a condition where individuals are infected by the intracellular bacteria without active disease but are at risk for reactivation, if their immune system fails. Here, we discuss the role of nonspecific inflammatory responses mediated by cytokines and chemokines induced by interaction of innate receptors expressed in macrophages and dendritic cells (DCs). We also review current information regarding the importance of several cytokines including IL-17/IL-23 in the development of protective cellular and antibody-mediated protective responses against Mtb and their influence in containment of the infection. Finally, in this paper, emphasis is placed on the mechanisms of failure of Mtb control, including the immune dysregulation induced by the treatment with biological drugs in different autoimmune diseases. Further functional studies, focused on the mechanisms involved in the early host-Mtb interactions and the interplay between host innate and acquired immunity against Mtb, may be helpful to improve the understanding of protective responses in the lung and in the development of novel therapeutic and prophylactic tools in TB.

Rare variants and HLA haplotypes associated in patients with neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals. In silico modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets.

Thinking Outside the Box: Innate- and B Cell-Memory Responses as Novel Protective Mechanisms Against Tuberculosis.

Tuberculosis (TB) is currently the deadliest infectious disease worldwide. Failure to create a highly effective vaccine has limited the control of the TB epidemic. Historically, the vaccine field has relied on the paradigm that IFN-γ-mediated CD4+ T cell memory responses are the principal correlate of protection in TB. Nonetheless, the demonstration that other cellular subsets offer protective memory responses against Mycobacterium tuberculosis (Mtb) is emerging. Among these are memory-like features of macrophages, myeloid cell precursors, natural killer (NK) cells, and innate lymphoid cells (ILCs). Additionally, the dynamics of B cell memory responses have been recently characterized at different stages of the clinical spectrum of Mtb infection, suggesting a role for B cells in human TB. A better understanding of the immune mechanisms underlying such responses is crucial to better comprehend protective immunity in TB. Furthermore, targeting immune compartments other than CD4+ T cells in TB vaccine strategies may benefit a significant proportion of patients co-infected with Mtb and the human immunodeficiency virus (HIV). Here, we summarize the memory responses of innate immune cells and B cells against Mtb and propose them as novel correlates of protection that could be harnessed in future vaccine development programs.

Aspartic acid70 in the HLA-DRB1 chain and shared epitope alleles partially explain the high prevalence of autoimmunity in Mexicans.

INTRODUCTION: Autoimmune thyroid disease (AITD) is the most common autoimmune disorder worldwide. Remarkably, it is commonly accompanied by other autoimmune diseases, such as rheumatoid arthritis (RA). The immunopathogenic mechanisms behind the coexistence of these disorders are still not completely understood. Immunogenetics influences the physiopathology of these diseases since ethnicity plays an essential role in the inheritance of susceptibility markers. METHODS: High-resolution HLA class II typing was performed using a sequence-based method. RESULTS: The allele frequency of HLA-DRB1∗04:04 and -DRB1∗03:01 were significantly increased in patients with AITD and RA compared to healthy individuals, pC â€‹= â€‹0.021, OR â€‹= â€‹2.4, 95%CI â€‹= â€‹1.19-4.75 and pC â€‹= â€‹0.009, OR â€‹= â€‹3.4, 95%CI â€‹= â€‹1.42-7.93, respectively. Remarkably, these patients have a combined risk given by susceptibility HLA-DRB1 alleles that contain the shared epitope, pC â€‹= â€‹0.03, OR â€‹= â€‹1.7, IC95% â€‹= â€‹1.07-2.76, and a lack of protective alleles carrying aspartic acid70, pC â€‹= â€‹0.009, OR â€‹= â€‹0.5, IC95% â€‹= â€‹0.32-0.84. DISCUSSION: The results suggest that patients with AITD and RA have an immunogenetic mechanism that combines the susceptibility alleles associated with both diseases. Importantly, it seems to be linked mainly to the lack of protective alleles with aspartic acid in the position 70, along with the presence of susceptibility alleles that have the sequences QRRAA, QKRAA, and RRRAA at positions 70-74. CONCLUSION: Patients with AITD and RA have a characteristic immunogenetic signature, which could be useful for determining multiple autoimmunities and assessing their relatives' risk of developing it.

The role of socioeconomic status in the susceptibility to develop systemic lupus erythematosus in Mexican patients.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well-identified as risk factors. SLE patients have different phenotypes or clinical presentations, which vary among Mexicans. This variation could be explained by ethnicity and admixture. Since socioeconomic status probably limits and change the patterns of migration, this factor could favor inbreeding and homogamy in some geographic areas. Consequently, it could alter or restrict the possibilities of admixture too. Therefore, the socioeconomic status may also have implications in the susceptibility and the clinical heterogeneity of SLE in Mexican patients. METHODS: One hundred twenty-three SLE patients and 234 healthy individuals with Mexican admixed ancestry were recruited. HLA alleles were analyzed using the HLA typing method based on Sequence-based typing (SBT). RESULTS: As expected, it was found an increased frequency of the HLA-DRB1*03:01 allele in all socioeconomic groups when compared with healthy individuals. The susceptibility allele found in the low-income SLE patients was HLA-DRB1*04:05 whereas, the susceptibility alleles for the high-income SLE patients were HLA-DRB1*07:01 (pC = 0.03, OR = 2.0) and HLA-DRB1*11:04 (pC = 0.0004, OR = 5.1). Additionally, the frequencies of two protective alleles HLA-DRB1*14:06 (pC = 0.01, OR = 0.28) and HLA-DRB1*16:02 (pC = 0.04, OR = 0.22) were found diminished. These findings correlate with the admixture differences between low-income and high-income SLE patients. The clinical manifestations showed a different distribution between both groups. Arthritis and neurological disorder were prevalent in low-income SLE patients, while the hematological disorder was prevalent in high-income SLE patients. CONCLUSIONS: These findings suggest that HLA class II DRB1 genes contribute to the susceptibility and protection to develop SLE differently depending on socioeconomic status. Due to this, the clinical manifestations vary among patients and it could be related to different admixture charge.Key Point• HLA class II DRB1 genes contribute to the susceptibility and protection to develop SLE differently depending on socioeconomic status.

Genetic diversity of HLA system in two populations from Puebla, Mexico: Puebla city and rural Puebla.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 2827 Mexicans from the state of Puebla living in the city of Puebla (N = 1994) and rural communities (N = 833), to obtain information regarding allelic and haplotypic frequencies. We found that the 16 most frequent haplotypes in Puebla are all of them Native American. Admixture estimates revealed that the main genetic components in the state of Puebla are Native American (72.21 ±â€¯1.25% by ML; 63.30% of Native American haplotypes) and European (21.05 ±â€¯1.92% by ML; 23.86% of European haplotypes), and a less prominent African genetic component (6.74 ±â€¯2.20% by ML; 6.20% of African haplotypes).

Genetic diversity of HLA system in two populations from Yucatán, Mexico: Mérida and rural Yucatán.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 324 Mexicans from the state of Yucatán living in the city of Mérida (N = 192) and rural communities (N = 132), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in the state of Yucatán include 16 Native American and one European haplotype. Admixture estimates revealed that the main genetic components in Yucatán are Native American (81.54 ±â€¯4.99% by ML; 62.92% of Native American haplotypes) and European (11.50 ±â€¯15.43% by ML; 23.26% of European haplotypes), and a less prominent African genetic component (6.96 ±â€¯10.47% by ML; 5.93% of African haplotypes).

Genetic diversity of HLA system in two populations from Quintana Roo, Mexico: Cancún and rural Quintana Roo.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 98 Mexicans from the state of Quintana Roo living in the city of Cancún (N = 48) and rural communities (N = 50), to obtain information regarding allelic and haplotypic frequencies and their linkage disequilibrium. We found that the most frequent haplotypes in Quintana Roo include ten Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in Quintana Roo are Native American (80.85 ±â€¯3.70% by ML; 60.20% of Native American haplotypes) and European (15.19 ±â€¯14.25% by ML; 26.02% of European haplotypes), and a less prominent African genetic component (3.96 ±â€¯10.75% by ML; 6.63% of African haplotypes).

Genetic diversity of HLA system in three populations from Sonora, Mexico: Ciudad Obregón, Hermosillo and rural Sonora.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 439 Mexicans from the state of Sonora living in Ciudad Obregón (N = 143), Hermosillo (N = 99), and rural communities (N = 197) to obtain information regarding allelic and haplotypic frequencies. We find that the 13 most frequent haplotypes for the state of Sonora include nine Native American, three European and one Asian haplotypes. Admixture estimates revealed that the main genetic components in the state of Sonora are European (51.25 ±â€¯2.90% by ML; 37.70% of European haplotypes) and Native American (43.35 ±â€¯2.57% by ML; 39.64% of Native American haplotypes), while the African genetic component was less apparent (5.39 ±â€¯2.54% by ML; 11.04% of African haplotypes).

Genetic diversity of HLA system in two populations from Campeche, Mexico: Campeche city and rural Campeche.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 81 Mexicans from the state of Campeche living in the city of Campeche (N = 34) and rural communities (N = 47), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes in the state of Campeche include ten Native American, three European, one African and one Asian haplotype. Admixture estimates revealed that the main genetic components in the state of Campeche are Native American (65.56 ±â€¯0.96% by ML; 51.24% of Native American haplotypes), European (34.44 ±â€¯10.94% by ML; 30.25% of European haplotypes), and a virtually absent African genetic component (0.00 ±â€¯10.31% by ML; 9.26% of African haplotypes).

Genetic diversity of HLA system in two populations from Oaxaca, Mexico: Oaxaca city and rural Oaxaca.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 636 Mexicans from the state of Oaxaca living in the city of Oaxaca (N = 151) and rural communities (N = 485), to obtain information regarding allelic and haplotypic frequencies. We found that the 13 most frequent haplotypes in Oaxaca are all of putative Native American origin. Admixture estimates revealed that the main genetic components in the state of Oaxaca are Native American (73.12 ±â€¯2.77% by ML; 61.52% of Native American haplotypes) and European (17.36 ±â€¯2.07% by ML; 20.69% of European haplotypes), and a relatively high African genetic component (9.52 ±â€¯0.88% by ML; 8.94% of African haplotypes).

Genetic diversity of HLA system in two populations from Tlaxcala, Mexico: Tlaxcala city and rural Tlaxcala.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 1011 Mexicans from the state of Tlaxcala residing in the city of Tlaxcala (N = 181) and rural communities (N = 830), to obtain information regarding allelic and haplotypic frequencies. We find that the ten most frequent haplotypes in Tlaxcala are all of Native American origin. Admixture estimates revealed that the main genetic components are Native American (75.13 ±â€¯1.56% by ML; 69.24% based on of Native American haplotypes) and European (16.10 ±â€¯4.98% by ML; 19.74% of European haplotypes), with a less prominent African genetic component (8.78 ±â€¯4.09% by ML; 4.35% of African haplotypes).

Genetic diversity of HLA system in two populations from Tabasco, Mexico: Villahermosa and rural Tabasco.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 224 Mexicans from the state of Tabasco living in the city of Villahermosa (N = 82) and rural communities (N = 142), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in Tabasco include 13 Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in Tabasco are Native American (67.79 ±â€¯1.59% by ML; 56.25% of Native American haplotypes) and European (27.21 ±â€¯3.97% by ML; 29.91% of European haplotypes), and a less prominent African genetic component (5.01 ±â€¯4.42% by ML; 8.93% of African haplotypes).

Genetic diversity of HLA system in three populations from Zacatecas, Mexico: Zacatecas city, Fresnillo and rural Zacatecas.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 453 Mexicans from the state of Zacatecas living in Zacatecas city (N = 84), Fresnillo (N = 103) and rural communities (N = 266) to obtain information regarding allelic and haplotypic frequencies and their linkage disequilibrium. We find that the most frequent haplotypes for the state of Zacatecas include seven Native American most probable ancestry (A*02 ∼ B*39 ∼ DRB1*04 ∼ DQB1*03:02; A*02 ∼ B*35 ∼ DRB1*08 ∼ DQB1*04; A*24 ∼ B*39 ∼ DRB1*14 ∼ DQB1*03:01; A*02 ∼ B*35 ∼ DRB1*04 ∼ DQB1*03:02; A*24 ∼ B*35 ∼ DRB1*04 ∼ DQB1*03:02; A*68 ∼ B*35 ∼ DRB1*04 ∼ DQB1*03:02 and A*24 ∼ B*35 ∼ DRB1*08 ∼ DQB1*04) and two European MPA haplotypes (HLA ∼ A*01 ∼ B*08 ∼ DRB1*03:01 ∼ DQB1*02 and A*29 ∼ B*44 ∼ DRB1*07 ∼ DQB1*02). Admixture estimates revealed that the main genetic components in the state of Zacatecas are European (47.61 ±â€¯1.85%) and Native American (44.74 ±â€¯1.12%), while the African genetic component was less apparent (7.65 ±â€¯1.12%). Our findings provide a starting point for the study of population immunogenetics of urban and rural populations from the state of Zacatecas and add to the growing knowledge on the population genetics of Northern Mexico.

Genetic diversity of HLA system in two populations from Nayarit, Mexico: Tepic and rural Nayarit.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 161 Mexicans from the state of Nayarit living in Tepic (N = 97) and rural communities (N = 64), to obtain information regarding allelic and haplotypic frequencies. We find that the ten most frequent haplotypes found in the state of Nayarit include eight Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in the state of Nayarit are Native American (50.79 ±â€¯5.03% by ML; 42.24% of Native American haplotypes) and European (37.04 ±â€¯6.21% by ML; 35.72% of European haplotypes), while African genetic component is less apparent but relatively high (12.17 ±â€¯2.50% by ML; 13.36% of African haplotypes).

Genetic diversity of HLA system in two populations from Colima, Mexico: Colima city and rural Colima.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 104 Mexicans from the state of Colima living in the city of Colima (N = 61) and rural communities (N = 43), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes in the state of Colima include eight Native American, two European and one African haplotype. Admixture estimates revealed that the main genetic components in the state are Native American (52.74 ±â€¯3.88% by ML; 48.10% of Native American haplotypes) and European (37.52 ±â€¯8.94% by ML; 26.66% of European haplotypes), and a relatively high African genetic component (9.74 ±â€¯8.40% by ML; 11.91% of African haplotypes).