As a pattern recognition receptor, TLR1 mediates innate immune responses to a variety of microbial cell wall components including bacterial lipoproteins. We have previously shown that the central region of the extracellular domain of human TLR1, comprising leucine-rich repeat (LRR) motifs 9–12, is required for the sensing of bacterial lipopeptides. In this study, we have investigated three nonsynonymous single nucleotide polymorphisms (SNPs) located in this region of TLR1 by generating these variants and examining receptor function. We have found that a variant of TLR1 based upon the SNP P315L, located in the loop of LRR motif 11 (LRR11), is greatly impaired in mediating responses to lipopeptides and a variety of other bacterial agonists for this receptor. Despite normal cell surface expression, the P315L variant also fails to bind to GD2.F4, a commonly used anti-TLR1 mAb. Although a number of amino acid substitutions at position 315 impair receptor function, the leucine substitution has the strongest deleterious effect. GD2.F4 inhibits agonist-induced activation of TLR1, supporting a crucial role for the loop of LRR11 in receptor function. These results also suggest that the P315L SNP may predispose certain individuals to infectious diseases for which the sensing of microbial cell components by TLR1 is critical to innate immune defense.

No abstract

This paper describes a study of a recent doomsday group and discusses the methodological problems which made this study an abortive attempt to test the proselyting hypothesis of Festinger, Riecken, and Schachter (1956). These problems included: unequivocally determining whether the doomsday group met the dissonance-theory specifications, demonstrating a change in the level of proselyting, difficulties typical of field-study research which stemmed from limitations of time, inaccessibility of information, and the occurrence of an unexpected and uncontrolled event. Two conclusions were drawn. (a) The required antecedent conditions for the post-disconfirmation proselyting effect are so numerous, qualitative and nonoperationally defined that they are unlikely to be met. (b) These problems, when compounded by the inevitable group differences which arise in field study, suggest that a valid and reliable negative research outcome regarding the proselyting hypothesis of dissonance theory is also unlikely. In other words, the proselyting hypothesis may not be disconfirmable—a prophecy which cannot fail.