Immune system pathophysiology

The main problem related to transplantation is graft rejection mediated by the host's immune system. When a person receives an organ from someone else during transplant surgery, that person's immune system may recognize that it is foreign. This is because the person's immune system detects that the antigens on the cells of the organ are different or not "matched." Mismatched organs, or organs that are not matched closely enough, can trigger a blood transfusion reaction or transplant rejection.

• To help prevent this reaction, doctors type, or match both the organ donor and the person who is receiving the organ. The more similar the antigens are between the donor and recipient, the less likely that the organ will be rejected. 
• Tissue typing ensures that the organ or tissue is as similar as possible to the tissues of the recipient. The match is usually not perfect. No two people, except identical twins, have identical tissue antigens.
• Doctors use medicines to suppress the recipient's immune system. The goal is to prevent the immune system from attacking the newly transplanted organ when the organ is not closely matched. If these medicines are not used, the body will almost always launch an immune response and destroy the foreign tissue.

Three classic forms of rejection exist:

1. Hyperacute antibody rejection - occurs a few minutes after the transplantation, when the antigens are completely unmatched. The tissue must be removed right away so the recipient does not die. This type of rejection is seen when a recipient is given the wrong type of blood. For example, when a person is given type A blood when he or she is type B.
2. Acute antibody rejection (T cell mediated and known as cellular rejection) - may occur any time from the first week after the transplant to 3 months afterward. It is initiated by the presentation of donor alloantigens to host T lymphocytes by antigen-presenting dendritic cells and macrophages; APCs^[1] may come from recipient or donor tissue. When the APCs are donor in origin, T-lymphocyte activation is said to occur via the direct pathway. When the APCs are the recipient’s innate cells, T lymphocyte activation is said to be via the indirect pathway, which resembles the pathway normally involved in the recognition of foreign substances.
3. Chronic antibody rejection - involves immune-mediated inflammatory injury to a graft that occurs over a prolonged period. It is most often due to the inability to maintain adequate immunosuppression necessary to control residual circulating antigraft T lymphocytes or antibodies. Chronic rejection manifests itself with a progressive decline in tissue function usually as a result of vascular injury and impaired blood supply

[1] APCs - antigen-presenting cells - A type of immune cell that boosts immune responses by showing antigens on its surface to other cells of the immune system. An antigen-presenting cell is a type of phagocyte.

Immunodeficiency is defined as an abnormality in one or more parts of the immune system that results in an increased susceptibility to disease states normally eliminated by a properly functioning immune response. Immunodeficiency syndromes can be classified as primary or secondary (acquired later in life).

Primary immunodeficiency disorders are either congenital or inherited as sex-linked, autosomal dominant, or autosomal recessive traits.

Causes:

Primary immunodeficiency diseases (PIDDs) are caused by genetic abnormalities of the immune system; this group consists of more than 130 distinct disorders.Most of these disorders are inherited as autosomal recessive traits, several are sex linked and caused by mutations in the X chromosome, and the causes of some have yet to be identified.

The root cause of many of PIDDs involves mutations that affect the signaling pathways (e.g., cytokines and cytokine signaling, receptor subunits, and metabolic pathways) that dictate immune cell development and function. Autoimmunity is frequently associated with PIDDs because the ability of the immune system to differentiate self from nonself is also affected.

Symptoms

One of the most common signs of primary immunodeficiency is having infections that are more frequent, longer lasting or harder to treat than are the infections of someone with a typical immune system. You may also get infections that a person with a healthy immune system likely wouldn't get (opportunistic infections).

Signs and symptoms of primary immunodeficiency can include:

• Frequent and recurrent pneumonia, bronchitis, sinus infections, ear infections, meningitis or skin infections
• Inflammation and infection of internal organs
• Blood disorders, such as low platelet count or anemia
• Digestive problems, such as cramping, loss of appetite, nausea and diarrhea
• Delayed growth and development
• Autoimmune disorders, such as lupus, rheumatoid arthritis or type 1 diabetes

https://www.mayoclinic.org/diseases-conditions/primary-immunodeficiency/symptoms-causes/syc-20376905

Hypersensitivity is defined as an abnormal and excessive response of the actrivated immune system that causes injury and damage to host tissues. Disorders caused by immune responses are collectively referred to as hypersensitivity reactions.

Hypersensitivity reactions are classified as one of four types:

1. Type I, IgE-mediated disorders;
2. Type II, antibody-mediated disorders;
3. Type III, complement-mediated immune disorders;
4. Type IV, T cell–mediated disorders

Type I hypersensitivity reactions are IgE-mediated reactions that develop rapidly upon exposure to an antigen. Type I hypersensitivity reactions represent the classic allergic response, and in this context, antigens are referred to as allergens.

Common allergens encountered include pollen proteins, house dust mites, animal dander, foods, household chemicals, and pharmaceutical agents like the antibiotic penicillin. Exposure to the allergen can be through inhalation, ingestion, injection, or skin contact.

Most type I hypersensitivity reactions develop in two distinct phases:

• a primary or initial, and
• a secondary phase or late phase.

Primary phase

The primary initial phase usually begins within 5 to 30 minutes of allergen exposure. It is mediated by acute mast cell degranulation and release of mediators. This phase is characterized by vasodilation, vascular leakage and smooth muscle contraction in response to mediators released such as histamine.

Secondary phase

The secondary or late phase follows the initial phase after several hours. It results from the action of lipid mediators and cytokines released from immune cells as part of the normal inflammatory response. Mast cells produce cytokines and chemotactic factors that promote migration of eosinophils and leukocytes to site of allergen exposure contributing to late phase response. The secondary phase is characterized by more intense infiltration with eosinophils and other inflammatory cells as well as tissue destruction.

Type I

Local allergic reaction, sneezing, itching, watery nose. If allergic reaction is severe it leads to anaphylaxis which is a serious life-threatening allergic reaction. Type I reactions may be localized to a discrete area or systemic causing significant disease such as asthma and life-threatening anaphylaxis

Type II, Antibody mediated disorders

Type II hypersensitivity reaction refers to an antibody-mediated immune reaction in which antibodies (IgG or IgM) are directed against cellular or extracellular matrix antigens, resulting in cellular destruction, functional loss, or tissue damage. If left untreated, patients may develop tissue or organ damage, which depends on the clinical presentation, e.g., cytopenias might contribute to infections, bleeding tendencies, and severe anemias. Acute rheumatic fever may lead to rheumatic heart disease with valvular lesions (stenosis and regurgitation).

Type III, Immune complex mediated disorders

Some of the complications associated with type III hypersensitivity reaction include:

 Serum Sickness

• Vasculitis
• Acute kidney injury, glomerulonephritis

Hypersensitivity Pneumonitis

• Alveolitis
• Pulmonary fibrosis/restrictive lung disease
• Cor pulmonale

Type IV, Cell mediated hypersensitivity disorders

Granulomatous diseases can affect any organ in the body, but for each type of granulomatous disease, there are common organs that are usually affected. For instance, sarcoidosis disease usually affects the lungs, eyes, and kidneys, resulting in pneumonia, lung fibrosis, pulmonary failure, cataracts, glaucoma, and kidney failure. In addition to the lungs, tuberculosis usually affects the vertebra and joints, resulting in back pain, joint stiffness, and arthritis.

The most common causes include medications like penicillin, thiazides, cephalosporins, and methyldopa. The drug molecule either binds to the surface of cells resulting in a neoantigen or alters the epitopes of the existing self-antigen on the cell surface. This directs the immune system to recognize modified antigens as foreign, with the breakdown of the immune tolerance and the production of antibodies directed to self-antigens.

https://www.ncbi.nlm.nih.gov/books/NBK563264/