A link science didn't catch

An unexpected immune interaction is probably sabotaging vaccines designed to treat cancer. A part of the body thought disconnected from the immune system actually interacts with it, which may explain some male infertility and certain autoimmune diseases.

The discovery of this unknown immune interaction comes less than two years after Jonathan Kipnis and Antoine Louveau of the University of Virginia Health System (UVA) rewrote the textbooks with their discovery that our brain has a direct connection to our immune system — a connection never thought to exist, which could have profound effects in the quest to defeat diseases ranging from Alzheimer's to multiple sclerosis.

Kenneth Tung MD, professor in the departments of pathology, microbiology, immunology, and cancer biology at the Beirne B. Carter Center for Immunology Research at UVA, believes many cancer vaccines are likely failing simply due to researchers picking the wrong antigen targets.

Tung and collaborators have discovered unexpected interaction between the testes and immune system.

While science textbooks insist a man's testes are barricaded from the immune system by an impenetrable wall of cells, research has now determined there's actually a very small door in that wall. Tung discovered that testes release antigens when producing sperm and antigens can ignite an immune response. As sperm production is a natural function of the body, the immune system ignores sperm antigens as non-lethal. This may explain why cancer vaccines designed to target antigens, are ignored by the immune system, and the vaccines fail.

The new work is published in Journal of Clinical Investigation.

"In essence, we believe testes antigens can be divided into those that are sequestered (behind an immune barrier) and those that are not. Un-sequestered antigens are not good candidates for cancer vaccine."

Kenneth Tung MD, Professor, Departments of Pathology, Microbiology, Immunology, and Cancer Biology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA.

The good news is that doctors can determine which antigens a patient's cancer cells release. By targeting antigens unnatural to the immune system, doctors may be able to greatly increase a vaccines' effectiveness.

The finding may also be important for infertile couples. Almost 12 percent of men who suffer from infertility have an autoimmune response to their own sperm, meaning their immune system literally attacks their own sperm. A particular step in the formation of sperm can determine whether sperm antigens will trigger such an immune response, and doctors may be able to target new treatments to avert the response.

Abstract
Autoimmune responses to meiotic germ cell antigens (MGCA) that are expressed on sperm and testis occur in human infertility and after vasectomy. Many MGCA are also expressed as cancer/testis antigens (CTA) in human cancers, but the tolerance status of MGCA has not been investigated. MGCA are considered to be uniformly immunogenic and nontolerogenic, and the prevailing view posits that MGCA are sequestered behind the Sertoli cell barrier in seminiferous tubules. Here, we have shown that only some murine MGCA are sequestered. Nonsequestered MCGA (NS-MGCA) egressed from normal tubules, as evidenced by their ability to interact with systemically injected antibodies and form localized immune complexes outside the Sertoli cell barrier. NS-MGCA derived from cell fragments that were discarded by spermatids during spermiation. They egressed as cargo in residual bodies and maintained Treg-dependent physiological tolerance. In contrast, sequestered MGCA (S-MGCA) were undetectable in residual bodies and were nontolerogenic. Unlike postvasectomy autoantibodies, which have been shown to mainly target S-MGCA, autoantibodies produced by normal mice with transient Treg depletion that developed autoimmune orchitis exclusively targeted NS-MGCA. We conclude that spermiation, a physiological checkpoint in spermatogenesis, determines the egress and tolerogenicity of MGCA. Our findings will affect target antigen selection in testis and sperm autoimmunity and the immune responses to CTA in male cancer patients.

Tung and his colleagues have published their findings in the Journal of Clinical Investigation. The research team consisted of Tung, of UVA's Department of Pathology, its Department of Microbiology, Immunology and Cancer Biology and its Beirne B. Carter Center for Immunology Research; Jessica Harakal; Hui Qiao; Claudia Rival; Jonathan C.H. Li; Alberta G.A. Paul: Karen Wheeler; Patcharin Pramoonjago; Constance M. Grafer; Wei Sun; Robert D. Sampson; Elissa W.P. Wong of the Center for Biomedical Research, Population Council; Prabhakara P. Reddi; Umesh S. Deshmukh; Daniel M. Hardy of Texas Tech University Health Sciences Center; Huanghui Tang of Northwestern University; C. Yan Cheng of the Center for Biomedical Research, Population Council; and Erwin Goldberg of Northwestern University.
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Mar 28, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Human sperm surround a human egg. In producing sperm, testes also
produce antigens which ignite an immune response.