Lecture Notes on the Immune System
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There are four broad categories under which diseases of the immune system can be placed. They are:
Small particles such as dust pollens. Foods, etc. may act as antigens in some people and elicit a variety of annoying responses. These range from itching and sinusitis to potentially fatal responses such as asthma. These hypersensitivity responses can occur through interaction with both humeral antibody or cell based immune mechanisms.
Hypersensitivity diseases are classified on the basis of the immunological mechanism, which mediates the response. There are four major types.
Always involves IgE antibody. Always have at least two exposures. Vasoactive and spasmogenic substances are released from mast cells and basophils that act on smooth muscle cells. Lots of inflammatory cells are involved; they are recruited by cytokines. Prototype disease is asthma. Always is a rapid response occurring within minutes after the second exposure.
During an exposure at an earlier time a person learns to make IgE antibodies to a specific antigen like pollen or cat dander. These IgE antibodies attach to Mast cells. Later when the person is exposed to the antigen again, the antigen will attach to the IgE antibody on the mast cells. This will stimulate the mast cell to release mediators of inflammation like histamine. The histamine is responsible for edema by its action on the endothelial cell, for contraction of smooth muscle cells (bronchial spasm in asthma), for mucous secretion and for recruitment of leukocytes which can prolong the reaction by releasing cytokines.
After a person is sensitized a person will have a reaction in 5 to 30 minutes. A late, second phase response can occur 2 to 8 hours after exposure and can last for several days. This late phase response involves most cells of the immune system such as eosinophils, monocytes and CD4 T-cells.
The differentiation of plasma cells that can make IgE is dependent on the CD4 cells (T2 subtype). The T2 cells control this differentiation by releasing interleukines (IL-4). When the mast cell is activated by the IgE antibody and antigen it will release mediators from its granules (histamine, enzymes such as proteases, and proteoglycans like heparin), and it will produce very strong secondary mediators from arachidonic acid in the membrane (leukotrienes, prostaglandins, platelet-activating factor and cytokines likeTNF and CSF). Eosinophils are very important in the late-phase response; they make the response stronger. This late stage response is very important in diseases like asthma and it can be effectively treated with anti-inflammatory drugs like steroids.
A person can have a systemic anaphylactic response or a local anaphylactic response. A local response is referred to as atopy. Forms of atopy are very diverse such as rash, sinusitis. Atopy implies a genetic predisposition to an allergen. About 10% of the population suffer from this type of allergies. A positive family history is found in 50% of people with atopy; these people seem to have high serum titer of IgE antibodies.
TYPE II HYPERSENSITIVITY
Humeral antibodies (IgM & IgG) target cells and predispose them to lysis or phagocytosis. Humeral antibodies are attracted to antigens on the cell surface or they may be attracted to exogenous antigens which are displayed on the cell surface. Disease prototypes are erythoblastosis fetalis, auto immune hemolytic anemia and Goodpastures syndrome.
After the antibody targets the cell, there are a number of ways that the cell can be killed.
TYPE III HYPERSENSITIVITY (IMMUNE COMPLEX DISEASE)
Antigen-antibody complex combines with activated complement, which attract neutrophils and elicits a strong inflammatory response. Prototypes are systemic lupus erythematosus (SLE), Arthus reaction, serum sickness and glomerularnephitis.
In systemic immune complex disease, also know as serum sickness because of the use of horse serum, the following happen in this sequence:
Local immune complex disease (Arthus reaction) is a localized area of tissue necrosis resulting from acute immune complex vasculitis. This reaction develops over a period of 4 to 10 hours and occurs with the first exposure to the antigen.
TYPE IV HYPERSENSITIVITY (CELL MEDIATED)
Sensitized T cells release lymphokines, which result in T cell mediated cytotoxicity. Prototypes are TB, contact dermatitis like poison ivy, transplant rejection.
The CD4 cells in this reaction are of the T1 subset.
There are two mechanisms for killing antigens:
1. Cytokines that are secreted form these cells. Antigens can be killed either by cytokines released from these cells (interferon [IFN] is very important, also TNF, CSF, etc.). Cytokines do the killing. Important against fungi, parasites tumor cell. In the mechanism associated with poison ivy and TB.
Isograft is tissue transplanted between genetically identical people like identical twins.
Allografts or isografts are transplants between the same species; human to human.
Xenografts are tissues transplanted between different species; pig skin to man.
When solid tissue (kidney, heart, liver) is transplanted from a donor to a recipient, the recipient will recognize the MHA class II on the donors cells and will mount an immune response in an attempt to reject the graft. Although we can perform complex surgery that allows us to place a donor organ in a recipient, we havenít learned how to out guess the immune system and keep it there for extended periods of time. Most transplants are allografts and thus we have to try and find two individuals who are genetically similar in terms of their MHC genes. Rejection is complex and involves both the humeral and cell mediated immune response.
There are three distinct forms of rejection:
The recipient already has antibodies against the donorís organ. This reaction can occur during surgery. The antibodies attack the endothelial cell of the blood vessels in the donor organ. This leads to thrombosis and rejection. Complement is also involved in this reaction.
This involves both antibodies and cell mediated immune reactions. The antibodies attack the vascular system. The cell-mediated response presents as a cellular infiltrate into the organ. Cells involved are CD4, CD8, macrophages and plasma cells. This response takes longer; usually occurs a couple of weeks after transplantation or when immunosuppressive treatment begins to fail. In general, cell based immunity is most important in graft rejection.
Involves both cell-mediated and humeral response. It is a slow rejection; it takes months to years. The donor cells that elicit the strongest response are the dendritic cell found in the organ transplant; they are very rich in MHC class I and class II antigens. A lot of fibrosis results in relation to chronic rejection.
Transplantation of Hematopoietic Cells and Graft-Versus-Host Reaction
In most cases when a person receives a bone marrow transplant, they are irradiated with lethal doses to destroy malignant cells or to create a graft bed (plastic anemia).
Graft versus host disease (GVH) occurs whenever immuncompetent cells are transplanted into an immunologically compromised host. GVH disease usually occurs with bone marrow transplants but can occur with solid tissue transplants if the solid tissue is rich in lymphatic cells (liver).
The lymphatic cells from the graft are the cells that have the immunological memory, and they perceive the host cells as non-self and they begin to attack.
GVH is mediated by T lymphocytes contained in the donorís bone marrow. Depletion of donor T cells before transplantation eliminates GVH disease, but when you eliminate donor T cells you decrease the chance of the graft failing. You need The T cells to establish the graft.
In some cases the bone marrow graft is rejected. T cells that survive in the irradiated host and NK cells mediate this reaction.
It is not uncommon to have autoantibodies in your serum, and in fact, the number of these increases as a person ages. This only makes sense because the body makes antibodies to damaged tissue. Pathology occurs in the form of autoimmunity when the body starts to make antibodies against normal healthy tissue of self-origin.
Three criteria have to be met in order for a disease to be classified as autoimmune.
Autoimmune diseases can be a reaction against a single organ of tissue or they can be systemic in nature. Here are just a few examples:
Single organ or cell type
Systemic Lupus erythematosus
Insulin-dependent diabetes mellitus
The symptom of autoimmune diseases is those of inflammation regardless of which organ is effect. If it is a systemic disease then the inflammation is more diffuse, involving more tissue.
There are a number of generalizations you can make regarding autoimmune diseases:
The question arises as to why the body suddenly starts attacking itself. There are many theories to explain this phenomenon. I will comment on a few of these.
Release of Sequestered Antigen
If an antigen is completely sequestered (walled off) from the immune system during development, it is most likely viewed as foreign when (and if) it is introduced into the circulation. Upon introduction to the immune system, the immune system recognizes it as non-self and starts to attack the healthy tissue. Spermatozoa and antigens from the lens and cornea of the eye fall in this category. Trauma to the eye of testicles can lead to this response. There is a higher incidence in men who have undergone vasectomy than in those who have not.
Some infectious agents (streptococci) have similar epitopes as self-antigens. An immune response against the organism my produce antibodies which cross-react with self-antigens. Rheumatic heart disease falls in this category. There is evidence that MS might also fall here as myelin protein might cross react with some viruses.
Failure of Activation-Induced Cell Death
This could result in a defect in the road to apoptosis. Damaged cells that normally would die via apoptosis can not die and are identified by the immune system as non-self.
Failure of T Cell-Mediated Suppression
This is related to a genetic defect in the ability of subset T2 CD4 cells to produce the cytokines that are needed to suppress the immune response (IL-10 and IL-4).
Breakdown of T-Cell Anergy or escape of the forbidden clone
T-cell anergy refers to irreversible inactivation of T-cells. This is induced during the encounter with antigens under certain conditions. It involves two signals. The second signalís molecules are not expressed on normal cells, which leads to anergy.
Clones of T-cells that have the ability to make antibodies against self are normally deleted due to the overwhelming presence of the antigen. Some of these clones escape suppression and start reacting against self. This is a very complex theory that claims that when there is major tissue necrosis and inflammation, antigen-presenting cells can express co-stimulatory molecules that up regulate the immune system.
Systemic Lupus Erythematosus is the prototype of autoimmune diseases.
IMMUNODEFICIENCY can be acquired (AIDS) or genetic.
Some genetic immunodeficiency diseases are:
ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)
Amyloidosis is a systemic disease and most likely a derangement of the immune system. Amyloid is an abnormal protein substance, deposited between cells in many tissues and organs. Because amyloid is deposited between the cells, it puts pressure on the adjacent cells and causes their atrophy. There are a number of different types of amyloid therefore amyloidosis is most likely a group of diseases.
There are 15 different kinds of amyloid but the most common are:
Amyloidosis can be either systemic or local (senile cerebral)
There are four broad classifications of systemic:
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