Kevan L. Hartshorn

Collectins and pulmonary innate immunity

Summary: The surfactant‐associated proteins SP‐A and SP‐D are members of a family of host defense lectins, designated collectins. There is increasing evidence that these pulmonary, epithelial‐derived proteins are important components of the innate immune response to microbial challenge and participate in other aspects of immune and inflammatory regulation within the lung. Both proteins bind to glycoconjugates and/or lipid moieties expressed by a wide variety of microorganisms, and to certain organic particles, such as pollens. SP‐A and SP‐D have the capacity to modulate leukocyte function and, in some circumstances, to opsonize and enhance the killing of microorganisms. The biologic activity of cell wall components, such as Gram‐negative bacterial polysaccharides, or viral glycoproteins, such as the hemagglutinin of influenza viruses, may be altered by interactions with collectins. In addition, complementary or cooperative interactions between SP‐A, SP‐D and other host defense lectins could contribute to the efficiency of this defense system. Collectins could play particularly important roles in settings of inadequate or impaired specific immunity, and acquired alterations in the levels of active collectins within the airspaces and distal airways may increase susceptibility to infection.

Ligand Specificity of Human Surfactant Protein D EXPRESSION OF A MUTANT TRIMERIC COLLECTIN THAT SHOWS ENHANCED INTERACTIONS WITH INFLUENZA A VIRUS

Surfactant protein D is a pattern recognition molecule that plays diverse roles in immune regulation and anti-microbial host defense. Its interactions with known ligands are calcium-dependent and involve binding to the trimeric, C-type carbohydrate recognition domain. Surfactant protein D preferentially binds to glucose and related sugars. However, CL-43, a bovine serum lectin, which evolved through duplication of the surfactant protein D gene in ruminants, prefers mannose and mannose-rich polysaccharides. Surfactant protein D is characterized by two relatively conserved motifs at the binding face, along the edges of the shallow carbohydrate-binding groove. For CL-43, sequence alignments demonstrate a basic insertion, Arg-Ala-Lys (RAK), immediately N-terminal to the first motif. We hypothesized that this insertion contributes to the differences in saccharide selectivity and host defense function and compared the activities of recombinant trimeric neck + carbohydrate recognition domains of human surfactant protein D (NCRD) with CL-43 (RCL-43-NCRD) and selected NCRD mutants. Insertion of the CL-43 RAK sequence or a control Ala-Ala-Ala sequence (AAA) into the corresponding position in NCRD increased the efficiency of binding to mannan and changed the inhibitory potencies of competing saccharides to more closely resemble those of CL-43. In addition, RAK resembled CL-43 in its greater capacity to inhibit the infectivity of influenza A virus and to increase uptake of influenza by neutrophils.

Is Alzheimer's Associated Amyloid Beta an Innate Immune Protein

There is now abundant evidence that chronic inflammation in the brain is central to the pathogenesis of Alzheimers disease (AD) and that this is precipitated through accumulation of amyloid beta (Aβ) peptides. In this review, we first outline this evidence and how specific receptors on microglia and monocyte/macrophages determine whether extracellular Aβ peptides can be cleared through non‐inflammato‐ ry phagocytosis or instead result in pro‐inflammatory cytokine generation. Most efforts of treatment for AD so far have focused on reduction of Aβ levels (in particular neurotoxic oligomers of Aβ1‐42) in the brain. Recent findings suggest an alternative approach in which pro‐inflammatory responses to Aβ peptides are targeted to reduce injury. Most recently evidence has come to light that Aβ peptides resemble anti‐ microbial peptides which are part of the innate defense system against infection. Such peptides act both by directly inactivating pathogens, but also by modulating respons‐ es of innate immune cells, including phagocytes. Indeed, Aβ peptides, particularly Aβ1‐42, do inhibit a range of potential pathogens, including bacteria, fungi, and viruses. Coupling this with evidence linking chronic viral, bacteria, or fungal infection to AD suggests that production of Aβ peptides in the brain is part of an innate immune response which might normally be beneficial, but which leads to harm when it is chronic or uncontrolled. This suggests that discovery of the original possibly infectious (or other inflammatory) stimulus for Aβ production would allow early intervention to prevent development of AD.