Immunological Tolerance Definition: Making sure antibodies or T cells recognizing self components are either eliminated or brought under tight control. Failure of tolerance can lead to autoimmunity. (Also applies to allergies.) Mechanisms: Clonal deletion of self-reactive T cells in thymus Regulatory T cells (Treg) Sequestered antigen Lack of danger signal from pathogens
Peripheral lymhoid tissue thymus T Cell Development in the Thymus Lymphoid stem cell CD8+ CD4+ CD4+ Treg CD8+ CTL + antigen Cytotoxic T lymphocyte CD4+ Th Helper T cell CD4+ Treg Regulatory T cell
Tolerance by Regulatory T cells (Treg) Blocked effector function Blocked effector function
Regulatory T cells can Inhibit Colitis Caused by Autoreactive T cells
Treg and Allergies Compared to the clear lungs of a normal mouse (left), the lungs of an egg-white-allergic mouse bcome inflamed when exposed to the allergen (middle). Infusing such a mouse with regulatory T cells before exposure blocks the inflammation (right). From Wickelgren, I. Science 306:596, 2004
Maternal Tolerance of the Fetus The fetus is a foreign graft because it has histocompatibility proteins from the father that differ from those of the mother.
Why is the Fetus Tolerated? Fetus is sequestered from the mother s tissue by placental tissue that is not recognized by the immune system Cells in the uterus and in the placenta secrete cytokines that tend to suppress inflammatory responses Regulatory T cells increase in the mother and suppress active immune responses against fetal antigens
How is Tolerance to Self Broken in the Initiation of Autoimmune Disease? Molecular mimicry
Guillain-Barre Syndrome A syndrome characterized by tingling, muscle weakness, and paralysis starting in the legs and moving to the arms Caused by an inflammation of the nerves due to autoimmune attack Auto-antibodies are pathogenic Often follows a minor infection (lung or gastrointestinal) In early stages of disease, plasmapheresis to remove antibodies from blood may help. Most people survive and recover completely.
Guillain-Barre Syndrome and Molecular Mimicry Campylobacter jejuni is a bacterium that causes gastroenteritis. The most common micro-organism that precedes Guillain-Barre syndrome Antibodies may be made to a membrane molecule in C. jejuni, that cross-react with the membrane molecules of human peripheral nerves Those antibodies then bind to human nerves, initiating an inflammatory response.
Mucosal Immune System
How Does the Intestine Defend Itself from Pathogens?
Antigen in the Lumen of the Intestine is Transported into Intestinal Tissue
The Intestinal Wall Is Associated with Immune System Cells
Immunoglobulin A (IgA) Can Protect against Pathogens in the Gut or Respiratory Tract
Cytotoxic T Lymphocytes Can Provide Protection Against Viruses
Gut Associated Lymphoid Tissue (GALT) The intestine is separated by a layer of only a few cells from the outside environment of the gut lumen M cells in the intestine sample antigen passing through the lumen Underneath the intestine surface are many kinds of immune system cells: CD8 T cells (CTL effectors & memory cells) CD4 T cells Plasma cells Dendritic Cells Mast cells
The oral route of antigen exposure leads to immunological tolerance
Gut Ecology The human gut is home to about 90 trillion microbes (commensal or beneficial), belonging to over 1000 species The gut-associated lymphoid tissue (GALT) does not produce an inflammatory response against these foreign antigens Likewise, the GALT does not ordinarily produce an inflammatory response against all the foreign antigens in food that pass through
Immune System in Intestine is Biased To Avoid Making Active Immune Response to Most Antigens The intestinal immune system tolerates normal gut flora (unless they enter mucosa following injury) Normal gut flora has an essential role in maintaining human health Interfere with pathogenic bacteria establishing infection Produce essential co-factors like Vitamin K Aid in digestion of dietary cellulose The normal flora influence the development of the immune system throughout the body Commensal bacteria induce a state of immune nonresponsiveness by inducing Treg
Why is Incidence of Allergies and Many Autoimmune Diseases Rising? Hygiene Hypothesis
Background to Joel Weinstock s Talk http://www.youtube.com/watch?v=adeviszfgue Prevalence of inflammatory bowel disease (IBD), an autoimmune disease, increased markedly in U.S. during 20 th century (from 1 in 10,000 to 1 in 250). Weinstock recognized that some worms infecting the intestine (helminths) did not induce inflammation, but instead calmed the host immune system. About 10 years after improved hygiene and deworming reduced worms in people, IBD rates jumped. Weinstock s hypothesis: after a long time evolving together, the human immune system came to depend on worm infection for proper functioning
A helminth parasite
Hookworm Eradication in Alabama
Worm Therapy for Autoimmune Disease Too many worms, or the wrong kind, can cause serious suffering or death Pig farmers are chronically exposed to pig whipworm (Trichuris suis), but have no apparent health problems. Weinstock performed two human clinical studies: Patients with Crohn s disease ingested 2,500 T. suis eggs at 3- week intervals for 24 weeks 23 of 29 Crohn s patients responded well; 21 went into complete remission 13 of 30 ulcerative colitis patients improved CAUTION: At present, there are companies that purportedly sell helminth therapy ; they are not approved and may be dangerous.
Rise in Allergic Diseases 9 to 16% (some estimates are 50%) of Americans have allergies In undeveloped countries, seasonal allergies are virtually unknown. In USA, seasonal allergies increased by 31% from 1985 to 1995. Childhood peanut allergies doubled from 1997 to 2002 Asthma increased from 35 cases per 1000 in 1982, to 56 cases per 1000 in 1994.