Welcome back to our series on Immunology and Food Allergies! Today we will revisit our definitions and talk about the different ways the immune system can fail in it’s ability to distinguish between self/non-self.

What autoimmune disorders, hypersensitivity disorders and allergies share in common is a breakdown of “tolerance,” which is the ability to ignore molecules that are not harmful or are part of the body (this is also referred to as the recognition of self/non-self). Autoimmune disorders specifically refer to the immune system identifying self antigens as foreign and attacking them and attacking those tissues. Examples include rheumatoid arthritis, multiple sclerosis and Type I diabetes. Hypersensitivity disorders occur when some commensal molecule is identified as foreign, and an allergy is a sub-class of hypersensitivity disorder, characterized by the presence of Immunoglobulin E (IgE) and immediate symptoms (see footnote 1 on the types of Ig). This distinction (between allergy and hypersensitivity in general) however, is only relevant in diagnosis and in an examination of the immune system’s response to the antigen, not to the search for tolerance, which is the equivalent of a cure, so going forward, I will be using the term “hypersensitivity” to refer to both allergy and non-allergy hypersensitivity disorders.From the reading I’ve done so far, there seem to be 5 main points of failure in tolerance and the distinction between self and non-self:

  1. Genetic defects in innate immune system cell receptors
  2. Bystander activation/affinity and issues with cytokine signaling
  3. T Cells binding to the wrong item. (also see bystander affinity)
  4. Mimicry from foreign infections
  5. Modification of cell surface antigens to be unrecognizable
  6. Failure of T-regulatory cells to target and eliminate immune cells that fail for the above four reasons

The innate immune system has self/non-self built into it’s receptors. The innate immune system has an estimated ~1000 distinct, receptors that are evolved into our very DNA. They consist of receptors designed to recognize various general classes of pathogens, such as a receptor that looks for flagellin, a protein used in a bacteria’s flagella used for locomotion, and receptors for general signs of cell/tissue damage or death, such as a receptor that recognizes histones (the proteins that wind up and help store DNA, presumably because if a protein that belongs in a cell’s nucleus is floating around in the blood stream or the lymph system then something is probably wrong). These are called Pathogen Associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs) respectively. These patterns are very old and very common. In fact, it the innate immune system as a whole goes as far back as fungi, and is vastly older than the adaptive immune system which is as old as vertebrates. For these reasons the innate immune system is unlikely (compared to the adaptive system) to have predispositions for an attack on self antigens. There are known genes in the innate immune system receptors where a particular allele will be associated with an auto-immune disorder, but for reasons we will see below, many more examples rest on the adaptive immune system.

2 and 3)
T-Helper cells in the adaptive immune system are responsible for presenting antigens to B lymphocytes, however a T Cell receptor, though closely related to antibodies (B Cells use antibodies as receptors), tends to have a specificity in the range of 10^-5-10^-7M, whereas antibodies have a range of 10^-7-10^-11 M, meaning that antibodies can be 10,000x more specific than T cell receptors (10,000 less likely to screw up). If a T-Helper cell presents the wrong protein however, these antibodies will specialize for the wrong substance. It will sometimes occur that when innate cells signal that an infection is underway, T cells will accidentally bind to a nearby self antigen, and present that to the B lymphocytes instead. This is called “bystander activation.” An example of bystander activation induced in the lab consisted of mice that were genetically engineered so that their insulin-producing cells carried on their surface a viral molecule. The mice were initially tolerant towards that protein until they were deliberately infected with the virus in question. The scientists observed that rapidly the insulin-producing cells were being killed off, and that they had effectively given the mice Type 1 diabetes. Other experiments have shown that injecting an antigen during an infection can induce hypersensitivity.

Some viruses will mimic cell proteins of the host so that the immune system will attack itself in the process. In the example of Multiple Sclerosis patients a virus that hides in the nerve tissue and mimics myelin stimulates an immune response that attacks the nerves. Attempts to treat Multiple Sclerosis by blocking the cytokine receptor that signals for more white blood cells to enter the deep nerve tissue lead to the sometimes fatal re-infection by the virus. This cause is apparent in autoimmune disorders like Multiple Sclerosis, but unlikely in the case of hypersensitivity, as pathogens have more incentive to mimic a host protein than a commensal foreign protein that may or may not be present in the body.

In some cases, modification of a cell’s surface receptors can render it no longer recognizable to the host immune system. It is speculated that this is the trigger for Rheumatoid Arthritis, where the immune system attacks the collagen in the joints. In a more mild and temporary example “contact” allergies like nickel and exposure to poison ivy yield the surface receptors in the skin cells unrecognizable by binding to them. Eventually the bond is broken (or the cell is killed) and the rash goes away.

In many of these cases, a full-blown pathology is associated with a weakening of the regulatory mechanism. There is research[2] suggesting that people with “farmer’s lung” (consisting of hypersensitivity to inhaled antigens) also have impaired T regulatory cells, as well as research suggesting Tregs play an important role in maintaining tolerance in successful organ transplants[3]. An attempt to amplify T-reg cells may yield the most immediate effect in treating pepple who have multiple hypersensitivities.

In future posts we’ll look at how the immune system regulates itself (and how that can be used to our advantage). We will also look at how genetic sequencing has been used to identify which of these six places are failing in individuals who have strong predispositions for various autoimmune diseases and hypersensitivities.

1. Blood serum can be divided into two types of proteins, albumins and globulins. “Antibodies” are immune system globulins,(see link 1) aka. Immunoglobulin (Ig for short), can be further divided into 5 subtypes, each given a letter. Because the person lettering them obviously didn’t understand the alphabet, they are IgA , IgD (a surface receptor on B cells), IgE (associated with allergy response as well as defense against helminthic parasites),IgG (the traditional antibody found floating in the bloodstream), IgM (specialized for mucusal surfaces).

1. Cellular and Molecular Immunology, 9e. Chapters (4,15,19 and 20) also available (and far more cheaply I might add) here.
(Most of the claims in this post reference one of these four chapters, I’m not sure the best way to cite it stylistically yet)
2. M. Girard, E. Israël-Assayag, Y. Cormier. 2011. Impaired function of regulatory T-cells in hypersensitivity pneumonitis. European Respiratory Journal
3. Qingyong Xu, Junglim Lee, Ewa Jankowska-Gan, et al. March 15, 2007. Human CD4+CD25low Adaptive T Regulatory Cells Suppress Delayed-Type Hypersensitivity during Transplant Tolerance. J Immunol.