Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis.

Abstract

The lymphocyte function-associated 1 (LFA-1), ~ Mac-l, and p150,95 molecules constitute a family of structurally and functionally related, high molecular weight, human leukocyte surface glycoproteins (1). Each molecule contains an a and a 3 subunit noncovalently associated in an al31 structure. The 3 subunits of Mr 95,000 in each of these three molecules are identical. The molecules are distinguished by their a subunits, which have different isoelectric points, molecular weights, and cell distributions, and are immunologically non-cross-reactive. The relative molecular weights of the Mac-l, LFA-1, and p150,95 a subunits are 165,000, 177,000, and 150,000 for aM, aL, and aX, respectively. This glycoprotein family is conserved in mouse and human (1, 2). In both species, the a and 3 subunits of each molecule are biosynthesized as separate a' and ~' intracellular precursors (1, 3). The precursors associate into a'~' complexes, are processed to the mature a3 form, and then transported to the cell surface. The murine aM and aL subunits have 33% amino acid sequence homology with one another. 2 Such homology suggests that a primordial a chain gene duplication event(s) led to the evolution of this glycoprotein family.The LFA-1 and Mac-1 molecules contribute to multiple types of leukocyte adhesion reactions. The LFA-1 molecule participates in the formation of adhesions between effector and target cells in cytolytic T lymphocyte-mediated killing and in natural killing, as shown by monoclonal antibody (mAb) blocking experiments (4-6). LFA-1 also participates in T helper cell responses, and its distribution on B cells, granulocytes, and monocytes suggests it may function in adhesion of these cells as well (7). Mac-1 has been defined (8) by mAb as a mouse differentiation antigen present on myeloid and absent on lymphoid cells. Subse-

Manifestations of Inflammatory Arthritis Are Critically Dependent on LFA-1

“…The leukocyte adhesion deficiency-I phenotype in humans and cattle (8,9,(42)(43)(44), as well as the defective T cell function and spontaneous skin ulceration seen in CD18 null mice emphasize that ␤ 2 integrins are critically important for host defense. Although LFA-1-deficient mice have deficits in experimental tumor models and increased mortality to gram (ϩ) sepsis with Streptococcus pneumoniae, they exist without apparent spontaneous illness in conventional mouse housing facilities (45,46).…”

“…Patients deficient in ␤ 2 integrin expression (the leukocyte adhesion deficiency-I phenotype) display leukocytosis, impaired wound healing, and particular susceptibility to recurrent microbial infection due in part to an inability to recruit leukocytes from the circulation and form pus (8,9). Mice deficient in CD18 (10) display a similar phenotype, with leukocytosis and susceptibility to bacterial infection (reviewed in Ref.…”

Complement genetics, deficiencies, and disease associations

“…C1-INH deficiency has been suggested to be associated with increased vascular permeability, thus oedema (Bracho, 2005). Current knowledge state that CR3 and CR4 deficiencies occur simultaneously in patients with leukocyte adhesion deficiency (LAD) type 1 due to genetic defects in the CD18 (β-subunit of both complement receptors) gene, ITGB2 (Springer et al, 1984(Springer et al, , 1986Roos et al, 2002;Bernard Cher et al, 2012). The lack of memory/effector CD8+ T cells and neutrophils in these patients result in reduced phagocytic response to bacteria and yeast.…”

“…The lack of memory/effector CD8+ T cells and neutrophils in these patients result in reduced phagocytic response to bacteria and yeast. Most clinical features are probably the result of CR3 deficiency of neutrophils and monocytes (Springer et al, 1984(Springer et al, , 1986. The reduced ability of such neutrophils to adhere to various substances, including complement-derived chemo-attractants (e.g.…”

The adhesion molecules of inflammation

“…Although these patients had a persistent leukocytosis, very few leukocytes accumulated at infected, necrotic lesions. In 1984 several groups demonstrated that these patients' leukocytes were missing CDt la,b,c/CD18 and subsequent work has demonstrated that the primary genetic defects are in CD18, the shared subunit (2)(3)(4)(5)23,24). Thus, the inability of leukocytes to adhere to endothelium or other particles because of an inherited defect in adhesive molecules prevents accumulation of leukocytes at sites of microbial invasion and results in severe, recurrent infections.…”