Complement receptor 1 (CR1, CD35) association with susceptibility to leprosy
Gabriela Canalli Kretzschmar1, Luana Caroline Oliveira1, Renato Mitsunori Nisihara2
1Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil.
Insights
Genetic variations in Complement Receptor 1 (CR1) increase leprosy susceptibility in Brazil. Specific CR1 haplotypes are linked to higher infection risk and altered immune responses, suggesting a key role in disease pathogenesis.
Area of Science:
- Immunogenetics
- Infectious Diseases Epidemiology
Background:
- Leprosy pathogenesis remains poorly understood, posing a significant public health challenge in Brazil.
- Complement Receptor 1 (CR1) plays a role in mycobacteria uptake by macrophages via complement fragment binding.
- Investigating CR1's role in leprosy susceptibility is crucial for understanding disease mechanisms.
Purpose of the Study:
- To investigate the association between CR1 gene polymorphisms and leprosy susceptibility in a Brazilian population.
- To analyze CR1 gene expression and soluble CR1 (sCR1) levels in leprosy patients.
- To elucidate the role of CR1 in differential susceptibility to various forms of leprosy.
Main Methods:
- A case-control study involving 213 leprosy patients and 297 controls.
- Haplotype analysis of nine CR1 polymorphisms using multiplex PCR-SSP.
- Quantification of CR1 mRNA levels by qPCR and soluble CR1 (sCR1) by ELISA.
Main Results:
- A common recombinant CR1 haplotype (rs3849266*T/rs3737002*T) significantly increased leprosy susceptibility (OR=2.43, p=0.017).
- This haplotype was associated with lower sCR1 levels in paucibacillary leprosy, potentially reducing anti-inflammatory responses.
- Another haplotype correlated with increased susceptibility to multibacillary leprosy (OR=3.04, p=0.01) and higher CR1 gene expression.
Conclusions:
- CR1 polymorphisms influence CR1 mRNA and sCR1 levels, impacting leprosy susceptibility.
- Haplotype-specific effects on CR1 function may enhance parasite phagocytosis and inflammation, contributing to disease development.
- CR1 appears to play a regulatory role in leprosy, influencing both susceptibility and potentially disease severity.
Background:
Pathophysiological mechanisms are still incompletely understood for leprosy, an urgent public health issue in Brazil. Complement receptor 1 (CR1) binds complement fragments C3b/C4b deposited on mycobacteria, mediating its entrance in macrophages. We investigated CR1 polymorphisms, gene expression and soluble CR1 levels in a case-control study with Brazilian leprosy patients, aiming to understand the role of this receptor in differential susceptibility to the disease.
Methodology:
Nine polymorphisms were haplotyped by multiplex PCR-SSP in 213 leprosy patients (47% multibacillary) and 297 controls. mRNA levels were measured by qPCR and sCR1 by ELISA, in up to 80 samples.
Principal Findings:
Individuals with the most common recombinant haplotype harboring rs3849266*T in intron 21 and rs3737002*T in exon 26 (encoding p.1408Met of the York Yka+ antigen), presented twice higher susceptibility to leprosy (OR = 2.43, p = 0.017). Paucibacillary patients with these variants presented lower sCR1 levels, thus reducing the anti-inflammatory response (p = 0.040 and p = 0.046, respectively). Furthermore, the most ancient haplotype increased susceptibility to the multibacillary clinical form (OR = 3.04, p = 0.01) and presented the intronic rs12034383*G allele, which was associated with higher gene expression (p = 0.043), probably increasing internalization of the parasite. Furthermore, there was an inverse correlation between the levels of sCR1 and mannose-binding lectin (initiator molecule of the lectin pathway of complement, recognized by CR1) (R = -0.52, p = 0.007).
Conclusions:
The results lead us to suggest a regulatory role for CR1 polymorphisms on mRNA and sCR1 levels, with haplotype-specific effects increasing susceptibility to leprosy, probably by enhancing parasite phagocytosis and inflammation.
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