Heterogeneous mutations in the β subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency

Kishimoto, Takashi; Hollander, Nurit; Roberts, Thomas M.; Anderson, Donald C.; Springer, Timothy A.

doi:10.1016/0092-8674(87)90215-7

Cited by 360 publications

(178 citation statements)

References 29 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Manifestations of Inflammatory Arthritis Are Critically Dependent on LFA-1

Watts

Beurskens

Martín‐Padura

et al. 2005

The Journal of Immunology

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Leukocyte infiltration of synovial fluid and tissues is the hallmark of inflammatory arthritis. Selectins and β2 integrins have been implicated in the multistep process of leukocyte adhesion to vascular endothelium. However, previous work has revealed disparate requirements for leukocyte recruitments to specific anatomic locales. Moreover, the mechanisms regulating recruitment of leukocytes to the joint in inflammatory arthritis models are not fully understood. We hypothesized that β2 integrins, expressed on leukocytes, might play a pathogenic role in synovial inflammation. Using mice deficient in all β2 integrins (CD18 null mice), we demonstrate that expression of these heterodimeric adhesion molecules is critical for arthritis induction in the K/B × N serum transfer model. Using null-allele mice and blocking mAbs, we demonstrate specifically that CD11a/CD18 (LFA-1) is absolutely required for the development of arthritis in this model. Blocking mAbs further revealed an ongoing requirement for LFA-1 I-domain adhesive function in disease perpetuation. These findings suggest that the LFA-1 I-domain forms an attractive target for treatment of human inflammatory arthritis.

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Section: Discussionmentioning

confidence: 99%

Manifestations of Inflammatory Arthritis Are Critically Dependent on LFA-1

Watts

Beurskens

Martín‐Padura

et al. 2005

The Journal of Immunology

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“…The whole phenomenon is mediated by the engagement of proadhesive molecules belonging to the ␤ 2 integrin subfamily (CD11/CD18), namely, CD11a/CD18 (LFA-1), CD11b/ CD18 (Mac-1, CR3), and CD11c/CD18 (gp150/95, CR4) (11). This is unequivocally proved by the finding that an inborn defect of CD18 expression, i.e., the type 1 leukocyte adhesion deficiency (LAD-1) syndrome (12), markedly impairs the TNF-induced activation of PMN in contact with biologic surfaces (1).…”

Section: Role Of Intracellular Chloride In the Reversiblementioning

confidence: 99%

Role of Intracellular Chloride in the Reversible Activation of Neutrophil β2 Integrins: A Lesson from TNF Stimulation

Menegazzi

Busetto

Cramer

et al. 2000

The Journal of Immunology

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The process of β2 integrin activation, which enhances the interaction of these heterodimers with ligands, plays a crucial role in the adherence-dependent neutrophilic polymorphonuclear leukocytes’ (PMN) responses to TNF. Our previous observation, showing that a marked decrease of the high basal Cl− content (Cl−i) is an essential step in the TNF-induced activation of PMN, stimulated this study, which investigates the role of alterations of Cl−i in the activation of β2 integrins triggered by TNF. Here we show that TNF enhances the expression of activation-specific neoepitopes of β2 integrins, namely, epitope 24, a unique epitope present on all three leukocyte integrin α subunits, and epitope CBRM1/5, localized to the I domain on the α-chain of Mac-1 (CD11bCD18). Moreover, we demonstrate that the conformational changes underlying the expression of the neoepitopes are dependent on a drop in Cl−i because 1) inhibition of Cl−i decrease is invariably accompanied by inhibition of β2 integrin activation, 2) Cl−i decrease induced by means other than agonist stimulation, i.e., by placing PMN in Cl−-free buffers, activates β2 integrins, and 3) restoration of the original Cl−i levels is accompanied by deactivation of β2 integrins. We also show that Cl−i decrease is required for TNF-induced cytoplasmic alkalinization, but such a rise in pHi does not seem to be relevant for β2 integrin activation. The results of our study emphasize the role of Cl− as a new PMN “second messenger.”

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“…There are four ␤ 2 integrins; ␣ L ␤ 2 (CD11a/CD18, LFA-1), ␣ M ␤ 2 (CD11b/CD18, Mac-1, CR3), ␣ x ␤ 2 (CD11c/CD18, p150,95), and ␣ d ␤ 2 (CD11d/ CD18) [5,6]. The importance of the ␤ 2 integrins in immune responses is underscored by the existence of a pathological condition, known as leukocyte adhesion deficiency (LAD), resulting in the loss of surface expression of the ␤ 2 integrins [7,8]. Patients with this disease suffer from recurrent lifethreatening bacterial infections.…”

Section: Introductionmentioning

confidence: 99%