When the Immune System goes wrong

• The immune system could fail in many ways. Some examples include:

  • failures in epithelial barriers, which could lead, for example, to skin infections
  • failure of phagocytes can lead to bacterial infections.
  • losing function of the complement system can result in bacterial infections.
  • failure in the proper production of antibodies or effector T-cells
  • sometimes, failure of the immune system can lead to heightened responses that also have negative consequences.
• The immune system is designed to protect the body from viruses, bacteria, parasites, and certain types of cancer.
• When the immune system goes wrong, it can result in:

  • hypersensitivity
  • autoimmunity
  • immunodeficiency
  • and cancer
• Hypersensitivity is the immune response to a harmless molecule that would be ignored by a healthy immune system, but in a malfunctioning immune system, would trigger a response that can lead to tissue death, or a fatal response.
• Things that can induce hypersensitivity are commonly encountered. These include things like pollen and a bee/wasp sting.
• Immediate hypersensitivity is when the response to the 'harmless molecule' is practically immediate, and immediate hypersensitivity is known/referred to as allergy.

  The allergic immune response is mediated by immunoglobulin E, mast cells, and Th2 receptors. The harmless molecule that induces immediate hypersensitivity/allergic reactions is called an allergen.
• The inherited tendency of an immediate hypersensitive/allergic response is known as atopy.
• The immediate hypersensitivity response is due to mast cell degranulation and histamine release, and when it happens in the skin, there is a wheal and flare.

  The wheal is a raised lesion in the skin.

  the flare is the redness surrounding a wheal.
• Allergy to pollen/hay fever develops when pollen grains are taken up by APCs, and processed and presented as peptides to CD4 T-cells. The activation of CD4 T-cells leads to the development of the Th2 response. Th2 cytokines, such as IL-4 & IL-5, and IL-13, are very potent, and activate specific B-cells. These B-cells will turn into plasma cells to produce the antibody specific to the IgE type, which is specific to pollen.
• Once the IgE antibodies (specific to pollen) have been produced, they bind to the surface of mast cells on the mucosal site. Pollen grains bind to (more than one) IgE antibodies in the process called cross-linking, which is results in the pollen grains being degranulated, and the inflammatory mediators diffuse out into the local area. This is what induces the sneezing in the nose, or wheal and flare reaction in the skin in hay fever.
• Common diseases that are classified as allergies/immediate hypersensitivity responses are:

  • asthma
  • perennial rhinitis (hay fever)
  • allergic eczema

  Rare diseases include anaphylaxis (often associated with bee/wasp stings, and can be fatal).
• Common therapies for immediate hypersensitivity responses are:

  • anti-histamines
  • beta-2-adrenoreceptor agonists to open up blood vessels
  • corticosteroids.

  Rarer therapies include:

  • desensitisation - patients are given repeated doses of the allergen via injections, or spraying under the tongue.
  • monoclonal antibodies that work against IgE.
• Desensitization development resulted from many experiments. One of them was an in-vivo switch to IL-10-secreting T-regulatory cells following exposure to a high dose of allergen. This was done on beekeepers, and seeing their inflammatory response to beestings over the course of years. The result was that the inflammatory response declined in a period of high number of bee stings. This desensitization was then adopted in therapeutic treatments.
• Immunological self tolerance is defined as the controlled failure to respond to self, despite having the capability to do so.

  When the processes that ensure immunological tolerance fail, it can lead to autoimmunity.
• Autoimmunity is defined as the loss of immunological tolerance to self components.

  Autoimmune diseases comes about if the loss of immunological tolerance is associated with pathology. The diseases are often accompanied by one or more manifestations of autoimmunity via T-cell or B-cell response. An example of this is an auto-antibody response.
• There is a spectrum of autoimmune disease that depend upon whether there is a single organ affected, or multiple organs affected. These two cases are termed organ specific and non-organ specific autoimmune diseases respectively.
• Examples of organ specific autoimmune diseases are type 1 diabetes (beta cells in the pancreas affected) and Grave's disease (increased functioning of the thyroid gland).

  Examples of non-organ specific autoimmune diseases are systemic lupus erythematosus, and rheumatoid arthritis (joints, skin, eye, lung, and spleen affected).
• One of the important manifestations of autoimmune disease a T-cell or B-cell autoimmune response. An example of this are serum autoantibodies, which are examples of breakage of self tolerance.

  • usually of the IgG class
  • important diagnostic tools
  • useful for monitoring disease activity
  • useful for predicting future disease
  • may be pathogenic
• Autoantibodies are useful diagnostically, but it's not always obvious what inks the antibody specificity with the pathology.

  For instance, rheumatoid factors work against rheumatoid arthritis, but they are actually antibodies against IgG.
• Two experiments can be done to prove whether a disease is an autoimmune disease or not:

  • Passively transfer the part suspected of causing the disease into a subject/recipient that doesn't have the disease.
  • Show that clinical responses can be obtained to immune suppression or to the re-establishment of tolerance.
• Examples of autoimmune diseases caused by autoantibodies are:

  • Graves' thyroiditis
  • and Myasthenia Gravis
• Graves' disease is an autoimmune thyroid disease (and the first disease to be associated with autoimmunity).

  Graves' disease is associated with inflammation behind the eyes, causing them to bulge in a process called proptosis. This can be one of the earliest manifestations of the disease.
• Graves' disease is the uncontrolled/unregulated production of thyroxin. An autoantibody is produced that binds to the TSH receptor on the thyrocyte and causes the thyroid gland to continue producing thyroxin. This leads to the symptoms of hyperthyroidism. As a result, there is a constant stimulation with no feedback loop.

  Patients experience fast heartbeat, hyperactivity, weight loss, bulging eyes because of the inflammatory foci behind the eyeballs, and an enlarged neck goitre.
• Normally, the pituitary gland produces thyroid stimulation hormone (TSH), which then binds to a TSH receptor on thyrocytes and drives the thyroid gland to produce the metabolic hormone thyroxin. When the correct amount of thyroxin is in the circulation, there is a negative feedback loop, where thyroxin will bind to the pituitary gland and prevent excess TSH production. This negative feedback loop to reduce/stop the production of thyroxin is what is impacted in Graves' disease.
• Myasthenia gravis affects communications across the neuromuscular junction. Usually, when a neuronal stimulus reaches the neuromuscular junction, acetylcholine is transmitted across the junction, binds to the Ach receptor and induces muscle contraction.

  In myasthenia gravis, transmission of Ach across the neuromuscular junction is impaired. Patients develop autoantibodies against the Ach receptor, which damage receptors on the muscular side of the junction. Hence, when the neuronal stimulus arrives, there is insufficient receptors to bind to Ach to induce muscle contraction.
• Patients with myasthenia gravis, because of the lack of sufficient Ach receptors to bind to Ach, will experience weakness and fatigue.
• One of the ways to prove whether a disease is an autoimmune disease, the immune effectors suspected of causing the disease can be taken and transferred into a subject that doesn't have the illness.
• During the last trimester of pregnancy, maternal IgG is transported across the placenta in order to protect the baby in their first weeks of life before the baby themselves is capable is making their own antibodies.
• If a pregnant mother has Graves' disease, she will have IgG autoantibodies against the TSH receptor. These autoantibodies can be transferred to the body in the last trimester of pregnancy, and this can result in the baby developing neonatal Graves' disease.

  This cross-placental transfer of disease manifestations from mother to foetus by IgG proves that the autoantibodies are the cause of the pathology. This is true for Graves disease and Myasthenia. Babies can be born floppy and unresponsive.
• Some autoimmune diseases are caused because the T-cell mediated response has been affected. In this case, the signs and symptoms of the autoimmune disease can be reduced by immunosuppressants. (Proving that a disease can be dealt with by immunosuppressants is another method of proving that the disease is an autoimmune disease). An example of this is rheumatoid arthritis.
• Immunosuppression of rheumatoid arthritis uses steroids and powerful monoclonal antibodies. These can reduce the inflammatory process.
• Type 1 diabetes is an autoimmune disease, and it's the progressive loss of insulin producing beta cells of the pancreas. This results in blood sugar levels not being regulated.

  Type 1 diabetes is associated with autoantibodies, it's T-cell mediated. This was determined because it was proven that administering humanized monoclonal antibodies against T-cells could be used as a therapy for Type 1 diabetes.
• Killing pancreatic beta cells is mediated by CD8 T-cells, and they are driven by an inflammatory process that is orchestrated by CD4 T-cells. This happens because Tregs (regulatory T-cells) failed to suppress the inflammation. Beta cells present autoantigens directly to CD8 T-cells, and that results in the beta cell being killed.
• The killing of beta cells is initiated and orchestrated when beta cell autoantigens are taken up by APCs and are presented to CD4 T-cells. When the CD4 T-cell is activated, it can differentiate into inflammatory Th1 & Th17 cells, and Th2 cells that cause the production of the autoantibodies that will kill the pancreatic beta cells.

  These inflammatory CD4 T-cells drive the CD8 T-cell response. This occur because regulatory T-cells aren't adequately supressing the inflammation.
• Immunodeficiency is when the protective quality of the immune system is lost. Immunodeficiencies can be divided into:

  • primary immunodeficiencies, which are rare and usually either an inherited defect or congenital abnormality
  • secondary immunodeficiencies, which are more common and are usually acquired.
• Cells of the immune system start from a pluripotent stem cell in the bone marrow that can give rise to at least 4 different lineages:

  • erythrocyte
  • platelets
  • lymphoid precursor cells
  • granulocytes/monocytes

  Monocytes and lymphoid precursor cells continue in their lineage. Monocytes become monoblasts, DC precursors, and granulocyte precursors. The lymphoid precursor cells become pre-B cells, pre-T cells, and Pre-NK cells. These then continue into the cells of the immune system.
• T-cells mature and develop in the thymus. In some cases, the thymus doesn't form, and in these cases, there are no T-cells in the blood or lymphatics. This is called Di George Syndrome. Di George Syndrome results from a failure in the correct development of the pharyngeal arches. As such, it's often associated with abnormalities affecting the heart and facial features, as well as immunodeficiency.
• Di George Syndrome is often diagnosed because of the other abnormalities. If not, it'll be picked up as an immunodeficiency state; the lack of T-cells leads to an increased risk of viral and bacterial infection. There will also be abnormal production of antibodies because B-cells no longer have T-helper/CD4 T-cells activating them.
• Immunodeficiency can be the result of a failure to correctly develop T-cells and B-cells. As a result of this, children will lack both in their early months of life. This disease state is called severe combine immunodeficiency (SCID).

  It is possible to use gene therapy to replace the molecules/cytokines missing.
• Neutrophils protect against bacterial infections by having several mechanisms that can directly kill bacterial cells themselves. One of the major bactericidal pathways involves the generation of reactive oxygen compounds, which are produced via a multi-step pathway involving several components. Some of these components can be impacted by signal gene defects. The disease that arises from these single gene defects is called chronic granulomatous disease. Neutrophils can surround bacterial cells, but they can't kill them.