CD32a AND CD32b: A BALANCING ACT TO GENERATE IMMUNITY OR TOLERANCE
Clinical reports show that polymorphisms in a receptor called CD32 influence the response to antibody therapy in cancer. In a paper appearing online on September 15 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Adam Boruchov and colleagues from Memorial Sloan Kettering Cancer Center dissect the contributions of CD32 isoforms in human dendritic cell (DC) activation and function.
The authors show that the ligation of CD32a induces DC maturation, exemplified by upregulation of maturation markers, release of specific cytokines and heightened T cell stimulatory capacity. In contrast, ligation of CD32b inhibits DC activation. These data uncover the differential contributions of CD32 isoforms and the potential role they may play in the induction of tolerance versus autoimmunity.
Further, the researchers show that intravenous immune globulin selectively shifts Fc-gamma receptor expression to a CD32b-dominated profile, which provides a mechanism to explain globulin's anti-inflammatory properties in humans. The findings also help account for results reported by some investigators when using mouse IgG with human dendritic cells. These findings have implications for optimizing the efficacy of therapeutic antibodies and suggest novel strategies for targeting antigens to the activating or inhibitory CD32 expressed on human Dcs to generate either antigen-specific immunity or tolerance.
TITLE: Activating and inhibitory IgG Fc receptors mediate opposing functions on human DCs
AUTHOR CONTACT:
Adam Boruchov
Memorial Sloan-Kettering Cancer Center, New York, NY USA
Phone: 212 639-5187; Fax: 212 937-2467; E-mail: boruchoa@mskcc.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24772
IMMUNOLOGY
MECHANISMS OF MONOCLONAL CD3 ANTIBODIES
Treatment with a therapeutic agent, called hOKT3g1(Ala-Ala) has been shown to prevent the loss of insulin production seen in Type 1 diabetes. But the mechanism of action of the drug was not clear from preclinical studies or from other similar agents. In a paper appearing online on September 15 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Kevan Herold and colleagues from Columbia University investigate how this drug, which is an anti-CD3 monoclonal antibody, works.
The authors previously found that patients who responded to drug therapy could be differentiated from non-responders by an increase in the number of CD8+ T cells after treatment, but the basis for this change was not known. Now, they show that the drug simulates proliferation of CD8+ but not CD4+ T cells and induces CD8+ cells with regulatory function. These findings suggest a novel mechanism that may account for the effects of the anti-CD3 monoclonal antibody in patients and can account for the lasting effect of a single course of drug treatment.
TITLE: Human T cell receptor signaling with modified anti-CD3 monoclonal antibody expands CD8+ T cells and induces regulatory CD8+CD25+ cells
AUTHOR CONTACT:
Kevan Herold
Columbia University, New York, NY USA
Phone: 212-305-3171; Fax: 212-3056486; E-mail: kh318@columbia.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=23961
PHYSIOLOGY
TLR2 GIVES THE KIDNEY A KICK
TLR2 is a protein that detects tissue damage and infection and is upregulated in the kidney after injury. The functional significance of this upregulation was unknown.
In a study appearing online on September 15 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Jaklien Leemans and colleagues from the University of Amsterdam show that endogenous TLR2 plays a proinflammatory and detrimental role in the kidney after renal ischemic injury in vivo.
This data gives new insight into the way the kidney functions in the absence of infection, and unravels the mechanism by which an inappropriate and subsequent detrimental inflammatory response in the kidney is induced. This study broadens the current concept of TLRs as being pathogen-associated pattern recognition receptors to a concept of TLRs as being surveillance receptors for both endogenous and exogenous molecules that indicate tissue injury and infection.
TITLE: Renal-associated toll-like receptor-2 mediates ischemia-reperfusion injury in the kidney
AUTHOR CONTACT:
Jaklien Leemans
University of Amsterdam, Amsterdam, Netherlands
Phone: +31-20-5665653; E-mail: j.c.leemans@amc.uva.nl
View the PDF of this article at: https://www.the-jci.org/article.php?id=22832
PHYSIOLOGY
SEEING THE LIGHT IN MACULAR DEGENERATION
Age-related macular degeneration (AMD) is the main cause of blindness in patients over the age of 60. In these AMD patients, choroidal neovascularization (CNV) is the most common cause of visual loss. The earliest clinically visible abnormality in AMD are extracellular deposits, called drusen. However, it was unclear which component of drusen contributes to AMD. Recent data demonstrated that amyloid-beta (Abeta) deposition was found in drusen from eyes with AMD.
In a paper appearing online on September 15 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Takeshi Yoshida and colleagues from the University of Tokyo show that Abeta contained in drusen plays an important role in the pathogenesis of AMD. These results suggest that approaches for clearing Abeta deposition might be an effective strategy against the development of AMD.
TITLE: The potential role of amyloid-beta in the pathogenesis of age-related macular degeneration.
AUTHOR CONTACT:
Kyoko Ohno-Matsui
Tokyo Medical and Dental University, Tokyo, Japan
Phone: 81-3-5803-5302; Fax: 81-3-3818-7188; E-mail: k.ohno.oph@tmd.ac.jp
View the PDF of this article at: https://www.the-jci.org/article.php?id=24635
PHYSIOLOGY
HOW HYPOPARATHYROIDISM HAPPENS
Hypoparathyroidism (HPT) is an inherited disorder linked to a chromosomal region that encodes three genes, but analyses thus far had not revealed any mutations. In a paper appearing online on September 15 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Rajesh Thakkar and colleagues from the University of Oxford conduct a detailed characterization of the X chromosome that contains the HPT region.
The researchers report the occurrence of a unique genetic abnormality that involves an interstitial molecular deletion-insertion. The importance of this in the genetic area is that it does not involve any coding regions of genes, and thus is likely to be altering regulatory regions. The identification of this unique deletion-insertion highlights the occurrence of a new genetic mechanism that is stably transmitted in the germ line to cause disease.
TITLE: An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism.
AUTHOR CONTACT:
Rajesh Thakker
University of Oxford, Oxford, Great Britain
Phone: 44 1865 857501; Fax: 44 1865 857502; E-mail: rajesh.thakker@ndm.ox.ac.uk
View the PDF of this article at: https://www.the-jci.org/article.php?id=24156
PHYSIOLOGY SKELETAL DISORDERS ARE IN THE GENES
The spondyloepimetaphyseal dysplasias (SEMDs) are a group of skeletal disorders characterized by defective growth of the spine and long bones of the body. The SEMDs can occur sporadically but heritable forms of the disease have been reported. In a paper appearing online on September 15 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Rakesh Thakkar and colleagues from the University of Oxford describe the chromosomal localization of the disease locus, by a genome wide search, and the analysis of a candidate gene (called matrix metalloprotease 13). The authors do functional studies in which the wild type and mutant matrix metalloprotease 13 were expressed. The results showed that SEMD is caused by a loss of function mutation in this matrix metalloprotease.
TITLE: Matrix Metalloproteinase 13 mutation causes Spondyloepimetaphyseal dysplasia, Missouri type (SEMDMO).
AUTHOR CONTACT:
Rajesh Thakker
University of Oxford, Oxford, Great Britain
Phone: 44 1865 857501; Fax: 44 1865 857502; E-mail: rajesh.thakker@ndm.ox.ac.uk
View the PDF of this article at: https://www.the-jci.org/article.php?id=22900
Journal
Journal of Clinical Investigation