The innate immune system is the first line of host defense against infection and is comprised of humoral and cellular mechanisms that recognize potential pathogens within minutes or hours of entry. The effector components of innate immunity include epithelial barriers, phagocytes and natural killer cells, as well as cytokines and the complement system. Complement plays an important role in the immediate response against microorganisms, including Streptococcus sp. The lectin pathway is one of three pathways by which the complement system can be activated. This pathway is initiated by the binding of mannose-binding lectin (MBL), collectin K-1 (CL-K1) and ficolins (Ficolin-1, Ficolin-2 and Ficolin-3) to microbial surface oligosaccharides and acetylated residues, respectively. Upon binding to target molecules, MBL, CL-K1 and ficolins form complexes with MBL-associated serine proteases 1 and 2 (MASP-1 and MASP-2), which cleave C4 and C2 forming the C3 convertase (C4b2a). Subsequent activation of complement cascade leads to opsonization, phagocytosis and lysis of target microorganisms through the formation of the membrane attack complex. In addition, activation of complement may induce several inflammatory effects, such as expression of adhesion molecules, chemotaxis and activation of leukocytes, release of reactive oxygen species and secretion of cytokines and chemokines. In this chapter, we review the general aspects of the structure, function and genetic polymorphism of lectin pathway components and discuss most recent understanding on the role of the lectin pathway in the predisposition and clinical progression of Rheumatic Fever (RF).

Background. Mannan-binding lectin (MBL), a soluble protein of innate immunity, is known to play a role in pathogen recognition and clearance. For mor

The mannose-binding lectin 2 (MBL2) gene is polymorphic and codes for a protein with an important role in the innate immune response, whose variants have been associated with a great number of diseases. Point variations have been described in the 5′ regulatory region at positions –550 (MBL2*H or *L) and –221 (*X or *Y), in the 5′ untranslated sequence at position +4 (*P or *Q), and in the coding sequence of exon 1 at codons 52, 54, and 57 (MBL2*A or D, A or B, and A or C, respectively). These can be in cis or in trans configuration. The different haplotypes influence the immunological phenotype of the individual, which makes MBL2 haplotyping very important. Previously described MBL2-typing methods do not present adequate haplotype resolution or are too complex and costly. We have developed a new MBL2-typing strategy that is economical and renders rapid and reliable results without ambiguities. We typed 202 individuals of European, 32 of African, and 16 of Oriental descent. Only five to six reactions from 10 possible PCR-SSPs (sequence-specific polymerase chain reactions) were sufficient to genotype one individual unambiguously. The reactions were specific for amplification of the variants located upstream of the coding sequence. The results were associated to the results of hybridizations of the amplified products with eight sequence-specific oligonucleotide probes (SSOP). The strategy led to identification of eight alleles: MBL2*HYPA, HYPD, LYPA, LYPB, LYPD, LYQA, LYQC, and LXPA. Their frequencies in each of the groups were similar to those of other populations studied to date, with MBL2*LYPD (g.[–550G>C; –221C>G; 4T>C; 223C>T; 230A>G; 239A>G]) being novel. All samples were found to be in Hardy-Weinberg equilibrium. Hum Mutat 19:296–306, 2002.

Transcriptomic research of blood cell lineages supports the understanding of distinct features of the immunopathology in human malaria. We used microarray hybridization, validated by real-time RT-PCR to analyze whole blood gene expression in healthy Gabonese children and children with various conditions of Plasmodium falciparum infection, including i) asymptomatic infection, ii) uncomplicated malaria, iii) malaria associated with severe anemia and iv) cerebral malaria. Our data indicate that the expression profile of 22 genes significantly differed among the investigated groups. Immunoglobulin production, complement regulation and IFN beta signaling, in particular IRF7 and ISRE binding signatures in the corresponding genes, were most conspicuous. Down-regulation in cerebral malaria seems to rely on AhRF, GABP and HIF1 hypoxia transcription factors. ARG1, BPI, CD163, IFI27, HP and TNFAIP6 transcript levels correlated positively with lactatemia, and negatively with hemoglobin concentrations. Differences in gene expression profile reflect distinct immunopathological mechanisms of P. falciparum infection. They emerge as potential prognostic markers for early therapeutic measures and need to be validated further. FUND: This work was supported by a grant of the NGFN (Nationales Genomforschungsnetz 01GS0114) and by a CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil) PhD scholarship for A. B. W. Boldt. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.