HLA Class I and Class II Conserved Extended Haplotypes and Their Fragments or Blocks in Mexicans: Implications for the Study of Genetic Diversity in Admixed Populations

Major histocompatibility complex (MHC) genes are highly polymorphic and informative in disease association, transplantation, and population genetics studies with particular importance in the understanding of human population diversity and evolution. The aim of this study was to describe the HLA diversity in Mexican admixed individuals. We studied the polymorphism of MHC class I (HLA-A, -B, -C), and class II (HLA-DRB1, -DQB1) genes using high-resolution sequence based typing (SBT) method and we structured the blocks and conserved extended haplotypes (CEHs) in 234 non-related admixed Mexican individuals (468 haplotypes) by a maximum likelihood method. We found that HLA blocks and CEHs are primarily from Amerindian and Caucasian origin, with smaller participation of African and recent Asian ancestry, demonstrating a great diversity of HLA blocks and CEHs in Mexicans from the central area of Mexico. We also analyzed the degree of admixture in this group using short tandem repeats (STRs) and HLA-B that correlated with the frequency of most probable ancestral HLA-C/−B and -DRB1/−DQB1 blocks and CEHs. Our results contribute to the analysis of the diversity and ancestral contribution of HLA class I and HLA class II alleles and haplotypes of Mexican admixed individuals from Mexico City. This work will help as a reference to improve future studies in Mexicans regarding allotransplantation, immune responses and disease associations

S100A8/A9 Proteins Mediate Neutrophilic Inflammation and Lung Pathology during Tuberculosis

Rationale: A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined. Objectives: The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB. Methods: The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques. Measurements and Main Results: We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB. Conclusions: Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB

Systemic Sclerosis Pathogenesis and Emerging Therapies, beyond the Fibroblast

Systemic sclerosis (SSc) is a complex rheumatologic autoimmune disease in which inflammation, fibrosis, and vasculopathy share several pathogenic pathways that lead to skin and internal organ damage. Recent findings regarding the participation and interaction of the innate and acquired immune system have led to a better understanding of the pathogenesis of the disease and to the identification of new therapeutic targets, many of which have been tested in preclinical and clinical trials with varying results. In this manuscript, we review the state of the art of the pathogenesis of this disease and discuss the main therapeutic targets related to each pathogenic mechanism that have been discovered so far

The Transcription Factor SCX is a Potential Serum Biomarker of Fibrotic Diseases

Fibrosing diseases are causes of morbidity and mortality around the world, and they are characterized by excessive extracellular matrix (ECM) accumulation. The bHLH transcription factor scleraxis (SCX) regulates the synthesis of ECM proteins in heart fibrosis. SCX expression was evaluated in lung fibroblasts and tissue derived from fibrotic disease patients and healthy controls. We also measured SCX in sera from 57 healthy controls, and 56 Idiopathic Pulmonary Fibrosis (IPF), 40 Hypersensitivity Pneumonitis (HP), and 100 Systemic Sclerosis (SSc) patients. We report high SCX expression in fibroblasts and tissue from IPF patients versus controls. High SCX-serum levels were observed in IPF (0.663 ± 0.559 ng/mL, p < 0.01) and SSc (0.611 ± 0.296 ng/mL, p < 0.001), versus controls (0.351 ± 0.207 ng/mL) and HP (0.323 ± 0.323 ng/mL). Serum levels of the SCX heterodimerization partner, TCF3, did not associate with fibrotic illness. IPF patients with severely affected respiratory capacities and late-stage SSc patients presenting anti-topoisomerase I antibodies and interstitial lung disease showed the highest SCX-serum levels. SCX gain-of-function induced the expression of alpha-smooth muscle actin (α-SMA/ACTA2) in fibroblasts when co-overexpressed with TCF3. As late and severe stages of the fibrotic processes correlated with high circulating SCX, we postulate it as a candidate biomarker of fibrosis and a potential therapeutic target

Frequencies of <i>HLA-C-B</i> blocks in 234 admixed Mexican individuals (468 haplotypes).

<p>Blocks of each ancestry (Amerindian, Caucasian, Caucasian shared with other populations, African, and Asian) were defined as those found in original populations with H.F. >1,0%, and not found in other native human groups in frequencies higher than 1,0%. We consider <i>t</i> value must be ≥2.0 to denote statistically significant association and thus validate Δ′ (shaded values).</p>*<p>Similar to B*35∶01 with a mutation at codon 207 ggc>tgc (Gly>Cys).</p>§<p>Similar to C*03∶04 with a mutation at codon 189 gtg>atg (Val>Met).</p

Allelic frequencies of <i>HLA-A, -B, -C, -DRB1</i>, and <i>-DQB1</i> in 234 Mexicans.

*<p>Similar to B*35∶01 with a mutation at codon 207 ggc>tgc (Gly>Cys).</p>§<p>Similar to C*03∶04 with a mutation at codon 189 gtg>atg (Val>Met).</p>†<p>Similar to DQB1*05∶02 with a silent mutation at codon 133 cgg>cga.</p

HLA Conserved Extended Haplotypes in 234 Mexican admixed individuals (468 haplotypes).

<p>HLA Conserved Extended Haplotypes in 234 Mexican admixed individuals (468 haplotypes).</p

Measures of genetic diversity at the allele level for HLA system in a Mexican admixed population.

<p>O.H.: Observed heterozygosity. E.H.: Expected Heterozygosity. <i>p</i> values <0.05 are considered statistically significative and thus reflect differences between O.H. and E.H. PIC: Polymorphism Information Contents. PD: Power of Discrimination.</p

Frequencies of <i>HLA-DRB1-DQB1</i> blocks in 234 Mexican admixed individuals (468 haplotypes).

<p>Blocks of each ancestry (Amerindian, Caucasian, Caucasian shared with other populations, African and Asian) were defined as those found in original populations with H.F. >1,0%, and not found in other native human groups in frequencies higher than 1,0%. We consider <i>t</i> value must be ≥2.0 to denote statistically significant association and thus validate Δ′ (shaded values).^† Similar to DQB1*05∶02 with a silent mutation at codon 133 cgg>cga.</p

Extension of HLA Conserved Extended Haplotypes to <i>HLA-A</i> in 234 Mexican Admixed individuals.

<p>Blocks of each ancestry (Amerindian, Caucasian, Caucasian shared with other populations, African and Asian) were defined as those found in original populations with H.F. >1,0%, and not found in other native human groups in frequencies higher than 1,0%. We consider <i>t</i> value must be ≥2.0 to denote statistically significant association and thus validate Δ′ (shaded values).</p