INNATE IMMUNE SYSTEM
The innate immune system has both a recognition function detecting bacterial products and an effector function attracting immune competent cells to the sites of tissue damage or bacterial entry. Macrophages, dendritic cells, neutrophils, and other cell populations express Toll-like receptors (TLRs), which mediate innate immune responses after interaction with pathogen-associated molecules patterns, such as LPS, peptidoglycan, and lipoteichoic acid. Toll-like receptors are a crucial link between the pathogen-associated molecules patterns and membrane-bound CD14, causing intracellular signaling with the translocation of the transcriptional regulatory factor nuclear factor κB into the nucleus. Nuclear factor κB participates in enhancing the expression of cytokines and other immunoregulatory mediators (32).
The LPS-binding protein (LBP) facilitates the transfer of bacterial LPS to the LPS receptor CD14 and TLR4. Therefore, LBP is of major importance in the host response to LPS and gram-negative bacteria. High systemic LBP levels were associated with sepsis severity, suggesting a significant role for this protein in sepsis (5).
In the proximal coding region of the LBP gene, a nonsynonymous SNP at position 292 (LBP-T292G) has been described. This polymorphism has been associated with an increased risk for sepsis among male septic patients (8). In contrast, the investigators found no association between a LBP-C1306T SNP and the development of septic complications (8). In another study, Barber and O'Keefe (7) stated that the LBP-T292G polymorphism does not exist; instead, the adjacent nucleotide was observed to be polymorphic (LBP-T291C), but without having an impact on septic complications and survival after multiple trauma.
Chien et al. (6) reported an association of an SNP in the promoter region of the LBP gene (LBP-C-836T) to higher median basal circulating LBP levels and increased gram-negative bacteremia-related morbidity. Furthermore, Flores et al. (5) described nine polymorphisms in the 5′-flanking region of the LBP gene (position -1978 to -763). None of these SNPs alone were associated with the incidence of severe sepsis. However, a haplotype analysis revealed that the common 4-SNP risk haplotype CATA (positions -1978/-921/-836/-763) was significantly associated with the susceptibility to severe sepsis in critically ill patients. Furthermore, LBP levels were significantly higher in homozygous carrier patients than in noncarriers (5).
CD14 initiates a response to gram-negative organisms by binding bacterial LPS. It functions as an anchor protein and enhances TLR4 responses (44). The soluble form of CD14 is also essential for TLR2 or TLR4 responses in cells that do not possess membrane-bound CD14 (45). Increased serum CD14 levels have been shown to correlate with shock and greater mortality in patients with gram-positive and gram-negative bacterial infections (46).
Genetic polymorphisms within the promoter region at positions -159 (CD14-C-159T) and -260 (CD14-C-260T) of the CD14 gene have been identified (13). The T/T allele of the CD14-C-159T polymorphism correlates with increased CD14 serum levels (13). There have been diverse studies associating the CD14-C-159T SNP with sepsis. Gibot et al. (14) found in a study with septic patients that the frequency of the TT genotype was higher in patients with sepsis and that the mortality rate in patients with the TT genotype was significantly increased when compared with patients with the CC or CT genotypes. Furthermore, another study confirmed that the T allele correlated with increased prevalence of gram-negative bacterial infections in critically ill patients (16). In a Chinese Han population, C allele was associated with a significantly reduced transcriptional activity of the promoter and a decrease of inducible sCD14 after multiple trauma. In addition, carriers of the C allele had a reduced risk to develop multiple organ dysfunction syndrome (MODS) or sepsis after multiple trauma (9). In contrast, Barber et al. (15) reported about a significant association between an increased risk for severe sepsis and the C allele after burn injury. Also in burn patients, carriage of the C allele was associated with an increased risk of death as compared with TT homozygotes. The authors assumed that a decreased level of CD14 expression among C allele carriers mechanistically results in a muted response to infection by gram-negative bacteria (17). Other studies did not find an association at all between the previously mentioned polymorphism and complications after sepsis (26, 47).
The CD14-C-260T polymorphism was reported to not affect the CD14 expression of unstimulated circulating monocytes or soluble CD14 plasma levels in healthy volunteers (10). In another study, the same authors also did not show an association between the CD14-C-260T polymorphism and an increased risk of severe sepsis in multiple trauma patients (11). In accordance, this SNP did not alter the overall risk for septic complications in critically ill patients (12).
The A allele of the CD14-G-1145A polymorphism resulted in a reduced transcriptional activity of the promoter and was associated with a decrease of inducible sCD14. Furthermore, the carriers of the A allele of this polymorphism demonstrated a reduced risk to develop MODS and sepsis after multiple trauma. The authors concluded that this polymorphism could serve as a biological risk predictor in trauma patients (9).
TLR2 and TLR4
TLR2 is predominantly responsible for recognizing gram-positive cell wall structures such as peptidoglycan, lipoteichoic acid, and lipoproteins (32).
A nonsynonymous SNP consists of a C/T substitution at nucleotide position 2029 within the start codon of TLR2 gene (TLR2-C2029T), changing arginine to tryptophan at position 677. In sepsis association studies, this SNP was associated with the susceptibility to develop severe infections (19, 32).
A second SNP within the start codon of TLR2 gene at position 2257 (TLR2-C2257T) leads to an amino-acid change from arginine to glutamine at position 753 (32). Lorenz et al. showed that this substitution was associated with a predisposition to severe bacterial infections (21). After multiple trauma, the allele frequency of the TLR2-C2257T polymorphism was significantly increased in African American patients with sepsis. However, the same authors found no such association for white American patients after severe trauma (22). In contrast, a study by Moore et al. (23) failed to show an association between the TLR2-C2257T SNP and morbidity or mortality caused by infection with Staphylococcus aureus.
In Chinese patients with major trauma, the T allele of the TLR2-C597T polymorphism and the A allele of the TLR2-A-15607G SNP were associated with in vitro cytokine (TNF-α, IL-8, and IL-10) production by peripheral blood leukocytes after LPS stimulation (18). In the same study population, the TLR2-C597T polymorphism was correlated to a higher sepsis morbidity rate and MOD scores (18). In critically ill patients, the C/C genotype of TLR2-C597T polymorphism was associated with pulmonary infection (20). The A/A genotype of the TLR2-A-16933A SNP was associated with an increased prevalence of sepsis and gram-positive bacteria. In contrast, the polymorphism was not associated with increased prevalence of septic shock or altered 28-day survival (16).
TLR4 as the central signaling receptor for LPS and its importance in the innate immune response to gram-negative bacteria have been elucidated in diverse experimental studies. In a mouse model of pneumonia, it was demonstrated that TLR-4-deficient mice had a reduced pulmonary clearance of Klebsiella pneumoniae and a profound increase in mortality when compared with mice with a functional TLR4 receptor (48-50).
Several SNPs have been identified in the TLR4 gene in humans. The TLR4-A896G polymorphism consists of a substitution of the conserved aspartic acid to glycine at position 299. The TLR4-C1196T SNP leads to the replacement of threonine to isoleucine at position 399 (32). These polymorphisms have been reported to influence TLR4 function and the innate host response. In a clinical study, the effects of inhaled endotoxin on lung function were investigated. Patients with the 299/399 polymorphisms were shown to be hyporesponsive to inhaled endotoxin (25). Agnese et al. (26) found that patients heterozygous for TLR4 299/399 polymorphisms had a significantly higher incidence of gram-negative bacterial infections compared with TLR4 wild types. Accordingly, the 299/399 alleles were more prevalent in patients with gram-negative bacterial infections and have been reported to be associated with septic shock (27). The significance of the TLR4-A896G polymorphism for the severity of posttraumatic sepsis was studied in severely injured white patients. The authors demonstrated that the carriage of the G allele was associated with a decreased risk of complicated sepsis. Furthermore, the G allele of TLR4-A896G SNP was demonstrated to be linked to a haplotype (htSNP4), which seems to confer a considerably reduced risk of complicated sepsis (51). The G allele of this polymorphism was also reported to be significantly associated with an increased risk for severe sepsis after burn injury (15).
In contrast, there have been several studies in which no association was shown between the 299/399 polymorphisms and sepsis (22, 32, 52). Specifically, the 299/399 polymorphisms did not influence the incidence of sepsis after surgery (20) or multiple trauma (22). Furthermore, in burn patients, no association between the TLR4-A896G polymorphism and burn-associated mortality was found (17).
In Chinese trauma patients, five TLR4 promoter SNPs at positions -2381, -2242, -1892, -1837, and -1418 were investigated. Only the C allele of the TLR4-T-2242C polymorphism was associated with a higher ex vivo TLR4 and TNF-α expression of peripheral blood leukocytes. Furthermore, this polymorphism was associated with an increased sepsis morbidity rate and MOD scores in multiple trauma patients (24). In another study, the same group found carriers of the C allele of the TLR4-G11367C polymorphism in the 3′ untranslated region of the TLR4 gene to be less likely to develop sepsis or MODS after major trauma. Furthermore, the C allele was associated with decreased synthesis of TNF-α and IL-6 ex vivo expression of peripheral blood leukocytes (28, 29).
Mannose-binding lectin (MBL) is an acute-phase protein that is involved in the innate immune responses. It binds carbohydrate structures on microbial surfaces and activates the "alternative" complement pathway (29).
Three different SNPs within the coding exon of the MBL gene have been described: MBL-C153T (amino-acid change: arginine to cysteine at position 52), MBL-G160A (amino-acid change: glycine to aspartic acid at position 54), and MBL-G169A (amino-acid change: glycine to glutamic acid at position 57) (53). The variant alleles were reported to be associated with low serum MBL levels and increased susceptibility to bacterial infections (32).
Furthermore, MBL-G-550C and MBL-G-221C polymorphisms in the promoter region of MBL gene have been reported (54). The G allele of MBL-G-221C and the wild-type alleles of MBL-C153T, MBL-G160A, and MBL-G169A were demonstrated to be associated to increased serum MBL levels. In contrast, the genetic variant alleles of MBL-G-221C, MBL-C153T, MBL-G160A, and MBL-G169A were associated to low systemic MBL levels (16). Different studies described an increase in the incidence of infection and sepsis when individuals have genetic variants, resulting in lower levels of MBL (16, 30, 31). However, no association between high- or low-MBL haplotypes with regard to survival was demonstrated (32).
Heat shock protein 70
Heat shock proteins (HSPs) are a class of proteins that are induced in response to trauma, infection, and inflammation. One major role of HSP is their action as chaperones, forming complexes that are recognized by the immune system following antigen presentation to T cells. Heat shock proteins also act like a cytokine and stimulate monocytic cells to produce proinflammatory mediators such as IL-6, TNF-α, and IL-1β. The 70-kd proteins are referred as HSP70 and their genes as HSPA. Three genes encoding proteins of the HSP 70-kd family lie in the class III region of the human major histocompatibility complex on chromosome 6: HSPA1A, HSPA1B, and HSPA1L (33, 55).
Especially, genetic polymorphisms within the promoter region of the encoding genes of HSP 70 have been identified like HSPA1B-C-179T, HSPA1B-G-1538A, and HSPA1L-C-2437T (32). In a study of Temple et al. (36), HSPA1A and HSPA1B mRNA expression of mononuclear cells was significantly increased in CT allele carriers of HSPA1B-C-179T polymorphism compared with CC homozygote individuals. Accordingly, in another study in septic shock patients, a HSPA1B-C-179T/HSPA1B-A1267G haplotype was associated with lower levels of HSPA1B mRNA and protein (56). Schröder et al. (33) observed the correlation between HSPA1B-G-1538A and HSPA1L-C-2437T promoter polymorphisms and outcomes in multiple trauma patients. Patients carrying the genotypes HSPA1B-G-1538A or HSPA1L-C-2437T had significantly higher plasma concentrations of TNF-α and IL-6 compared with those with genotype GG or TT. Whereas the HSPA1B-G-1538A polymorphism was not associated with outcome in this patient population, the presence of the HSPA1L-C-2437T genotype was a significant risk factor to develop liver failure (33). In contrast, a study by Schroeder et al. (34), investigating the significance of the HSPA1B-G-1538A polymorphism and the HSPA1L-C-2437T SNP in patients with severe sepsis, failed to show an association with the susceptibility to infection or survival in patients with severe sepsis. This result was confirmed in critically ill surgical patients (35).
OTHER INFLAMMATORY MEDIATORS
Procalcitonin (PCT) is a peptide precursor of the hormone calcitonin. It has been demonstrated as a reliable marker for the diagnosis of sepsis. Early elevated PCT levels have also been correlated with the development of posttraumatic complications (e.g., MODS, mortality) (37, 57). Furthermore, it is supposed to contribute significantly to the deleterious effects of systemic inflammation as a mediator. In experimental sepsis models, PCT administration resulted in an increased mortality rate, whereas treatment with a PCT-reactive antiserum increased survival (37, 57). The calcitonin gene (CALCA-1) on chromosome 11 is responsible for the synthesis of PCT (57).
Diverse CALCA-1 polymorphisms have been identified, e.g., CALCA-1-A-1787G (rs3781719), CALCA-1-A3617T (rs2956), and CALCA-1-A3740G (rs5242). In a prospective study, no significant associations between these genetic polymorphisms and posttraumatic incidence of MODS, acute respiratory distress syndrome (ARDS), and sepsis are described. Furthermore, no influence on systemic PCT concentrations was observed in multiple trauma patients (37). In contrast, several other studies found associations between polymorphisms of the CALCA gene and a number of diseases such as ovarian cancer, osteopenia, and hypertension (58, 59). This differences might be explained by the different origin of the underlying diseases (inflammatory vs. noninflammatory) and the different effects of PCT under those conditions. Under neoplastic conditions, increased systemic PCT levels do not seem to be detrimental, nor are there any observable clinical effects (57). These effects are in contrast to the potentially negative effects of PCT in patients with severe systemic inflammatory conditions, such as multiple trauma or sepsis (37). The authors postulated that the presence of cytokines (such as TNF-α, IL-6) in the CALCA gene promoter might override the tissue-selective expression pattern upon a specific stimulus, thereby significantly influencing the response to systemic inflammation (60). These effects of inflammatory mediators on the CALCA gene possibly result in a decreased importance of polymorphisms within the CALCA gene compared with the noninflammatory situation (37).
Angiopoietin 2 (Ang-2) is a vascular growth factor that is able to destabilize blood vessels, to enhance vascular leakage, and to prime the endothelium to respond to angiogenetic and inflammatory cytokines in acute lung injury (ALI), ARDS, and sepsis. Furthermore, increased circulating Ang-2 concentrations have been observed in patients with ALI and sepsis, which have also been correlated with mortality (38).
Several SNPs within the Ang-2 gene (ANGPT2), located on chromosome 8, have been identified. The ANGPT2-C32016T polymorphism (rs2515475) and ANGPT2-A28889C (rs2959811) SNP were reported to be associated to an increased risk for ARDS development, particularly in patients with extrapulmonary injuries (38). The same study identified an association between the CCTGG haplotype (ANGPT2-A59275G [rs2916702], ANGPT2-A56605G [rs2442468], ANGPT2-A53153G [rs2442635], ANGPT2-A454411G [rs2515435], ANGPT2-A34169G [rs2515466]) and an increased incidence of ARDS (38). Furthermore, carriers of the haplotype TT ANGPT2-A32016G and ANGPT2-A28889G had an increased risk to develop ARDS. The authors speculated that ARDS development was more likely to depend on linkage disequilibrium than on associations of individual SNPs (38).
Myosin light-chain kinase
Myosin light-chain kinase (MLCK) has been demonstrated to be a major determinant of apoptosis, leukocyte diapedesis, and lung vascular permeability in ALI (61). The MLCK is encoded by MYLK, a gene located on chromosome 3. MYLK encodes three isoforms of MLCK. The largest protein is the non-smooth muscle isoform (nmMLCK). Furthermore, the smooth muscle isoform and telokin, a protein involved in myosin binding, are encoded by MYLK (39). Gao et al. (62) found more than 50 SNPs within the MYLK gene. In a study including a trauma population at risk for ALI, Christie et al. (39) found that African American, but not European American, patients who developed ALI demonstrated greater frequencies of either the CC genotype of MYLK-G61T polymorphism (rs28497577) or the TT genotype of MYLK-A54795G SNP (rs9840993). Furthermore, they found that the CC genotype MYLK-A59850G (rs4678047) was protective for ALI in these individuals. Haplotype analysis in African Americans demonstrated an association between posttraumatic ALI and haplotypes composed of SNPs MYLK-C16421T (rs4678062) and MYLK-G61T (rs28497577). The strongest association was detected for the haplotype CGAT consisting of MYLK-C28717G (rs36025624), MYLK-C16421T (rs4678062), MYLK-G61T (rs28497577), and MYLK-A9264G (rs11707609). Therefore, it was suggested that the MYLK gene is an important candidate gene and that MYLK SNPs contribute to the risk of posttraumatic ALI in African Americans (39). Interestingly, the effects of MYLK SNPs after trauma were opposite to the effects observed in sepsis-induced ALI. In African American patients, individuals with the C allele of MYLK-A54795G SNP had an increased risk for sepsis-mediated ALI (62). In contrast, after trauma, the TT genotype at this locus conferred a significantly increased risk of ALI in African Americans. Similarly, the CC genotype of the MYLK-G61T polymorphism influenced trauma-mediated ALI risk, whereas septic ALI was associated with an increased risk with an A allele at this position (39). The divergent effects of the MYLK SNPs in trauma- and sepsis-induced ALI were explained with differences in the pathophysiology of ALI after major trauma and sepsis. Furthermore, it has to be considered that the risk for development of ALI is most likely multifactorial and mediated by more than a single genotype or mediator. Combinations of genotypes and interaction of genes in related pathways are therefore most likely to mediate risk of posttraumatic lung injury (39).
Mutations have also been identified within the mitochondrial genome. Mutations with an effect on mitochondrial function are of special interest in the setting of multiple trauma and sepsis due to the significant energy requirements under these conditions. The C allele of an SNP in the nicotinamide adenine dinucleotide dehydrogenase 1 (ND 1) gene at position 4216 (ND 1-T4216C) has been associated with numerous diseases and is believed to impair adenosine triphosphate production by the electron transport system (40, 42). In multiple trauma patients, carriage of the C allele was associated with an increased risk for infectious complications and death after severe trauma (40, 41). These results were confirmed after burn injuries with an increased incidence of complicated sepsis in carriers of the C allele. Furthermore, a significant association between the C allele and pulmonary failure was found (42). In contrast, in critically ill patients, the T allele of the ND 1-T4216C polymorphism has been associated with increased risk in various disease states (41).
Genetic association studies in multiple trauma and septic patients have in part demonstrated contradictory evidence of an effect from individual polymorphisms. It was postulated that methodological shortcomings (experimental design, statistical analysis, study size, power) might result in false-negative associations, thereby explaining the inconsistent evidence for a genetic effect on outcome after multiple trauma and sepsis (63).
It has been suggested that the nature of these studies requires a more rigorous statistical approach than the conventional significance of P < 0.05 (63, 64). This is due to the high number of human genes encoding for immune response substances (about 3,000) with a large number of possible variants and the low likelihood that a single polymorphism will have a significant effect on outcome in complex diseases such as multiple trauma and sepsis (29, 63). Even a P = 0.001 in a study of a highly probable candidate gene in 200 cases and 200 controls would be still likely a false-positive result. Only in 2,000 cases and controls a positive association with more than 50% can be assumed (63). This number of included patients has not been reached by the vast majority of the studies. Further possible reasons for the inconsistent results of genetic association studies are environmental factors in the heterogeneous trauma population (injury severity, age, site of infection), techniques of the genetic analysis, and the matching process between cases and controls (population stratification) (29, 63). Furthermore, Sutherland and Walley (29) suggested that the limited knowledge of transcriptional regulation and the structure of linkage disequlibrium may in part be responsible for the lack of reproducibility of many genetic studies after multiple trauma and sepsis. These authors supposed a haplotype-based approach to candidate gene association studies to avoid presumptions about the functional significance of SNPs in candidate genes.
Studies investigating the genetic predisposition for complications after multiple trauma and sepsis have provided evidence for a genetic heterogeneity in the posttraumatic immune response. The associated differences in response to multiple trauma may contribute to the development of new genetically tailored diagnostic and therapeutic interventions that may improve outcome in this patient population. In addition, detrimental adverse effects of adjuvant therapy could be avoided in other patients who, by genotype, are predicted not to benefit.
However, the robustness of individual SNPs to predict the predisposition for posttraumatic complications has to be questioned, because many SNP/disease associations are not reproducible in other cohorts. Therefore, it will be important for future genetic association studies to have adequate statistical power to identify whether an association between a particular genotype and clinical outcome exists. Furthermore, as the development of complications after multiple trauma is a multifactorial syndrome, it is unlikely that one polymorphism will result in a particular phenotype. Therefore, haplotypes are more likely to be associated with the posttraumatic outcome. However, it remains unclear how many SNPs and haplotypes are needed to provide individual and reliable risk estimation. This will be the task of further genome-wide association studies.
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Single-nucleotide polymorphism; innate immune system; inflammatory mediators; multiple trauma; posttraumatic complications