Autoimmune Disease of the Kidneys

There are various ways that the human immune system protects the body from autoimmune disease such as physical barriers, specificity, and regulatory mechanisms. A break in any of these protective mechanisms can lead to an autoimmune disorder. One such disorder is known as Glomerulonephritis (glom-er-u-lo-ne-FRY-tis). According to Seyed-Ali Sadjadi, M.D author of “Glomerulonephritis (nephritic syndrome)” “Glomerulonephritis (nephritic syndrome) is a disorder of glomeruli (clusters of microscopic blood vessels in the kidneys with small pores through which blood is filtered). It is characterized by body tissue swelling (edema), high blood pressure, and the presence of red blood cells in the urine” (1). There is little known about the underlying causes of Glomerulonephritis, but it is generally understood that the main culprit is a malfunction in the immune system’s protective mechanisms. When there is an abnormal alteration to the immune system components this can lead to a severe autoimmune disease such as Glomerulonephritis.

The normal function of the immune system has two different mechanisms, innate immunity and acquired immunity. Innate immunity involves physical barriers, chemical factors, secretions etc. This is the first line of defense that invading pathogens will encounter. According to the text, Intro to Immunology written by Karen Newell, Ph.D. “The innate response is characterized by the features of being immediate, of being inherent […], and of being relatively ‘antigen-non-specific’” (5). The innate response includes skin, hair, pH, secretions, involuntary muscle movement, etc. These elements of the innate response allow for the body’s immediate protection from harm. For example, skin can physically prevent pathogens from entering the body and the blood stream. Secretions such as blood after a person cuts him or her-self can force out invading bacteria or viruses, and coughing can help to release invading pathogens in the lungs.
Adaptive immunity is distinguished from innate immunity largely by the specificity of this mechanism. Newell adds, “Specific cells with receptors that are specific for antigens initiate the adaptive response” (5). This means that the cells involved with the adaptive response will react only to a specific antigen at a cellular level, in contrast to the innate immune response which will protect the body from many different kinds of pathogens at a surface level. Another element to adaptive immunity that distinguishes it from innate immunity is the element of “memory” which means that after the immune system is exposed to a specific pathogen the immune system will mount a response that will take time to develop, and a person will get sick. Memory allows the immune system to mount a quick response to the same pathogen the next time the person is exposed so that they become immune.

Adaptive immunity originates with the birth of two groups of white blood cells in the bone marrow, the T-Lymphocyte cells and B-Lymphocyte cells. After the birth of T-Cells and B-Cells in the bone marrow eventually the T-cells will migrate to the thymus where they are taught to differentiate into two types of cells; CD8 Killer T-Cells or CD4 Helper T-cells. B-Cells will remain in the bone marrow to mature. As Gene Mayer, Ph.D., author of “Immunology: Innate (Non-Specific) Immunity” states, “For T cell development the precursor T cells must migrate to the thymus where they undergo differentiation into two distinct types of T cells, the CD4+ T helper cell and the CD8+ pre-cytotoxic T cell” (1). During the maturation process in the Thymus, DNA recombination occurs when two proteins RAG 1 and RAG 2 dimerize and become activated to give the T-cell receptor alpha and beta variable chains, and alpha and beta constant chains that will recognize a specific MHC/antigen loaded complex located on an antigen processing and presenting cell, such as the B-Lymphocyte.

Both CD8 and CD4 are present on T-cells, but in order for the T-cell to become either a CD4+ helper T-cell or a CD8+ killer T-cell, one must be down regulated before the cell fully matures. The cell must also be equipped with co-stimulatory molecules to work properly. After the cell matures, it undergoes positive selection where the cell is tested to see if it can recognize antigens on MHC molecules. According to an article “T Cells” by David Wagner, Ph.D., “CD4+ T-cells recognize antigens presented by MHC class II. CD8+ T-cells recognize antigens presented by MHC class I molecules” (3). All nucleated cells will have MHC I because it has the potential to become infected or damaged. It is important for the T-cells to be able to recognize the correct MHC complex.

During the maturation process, if the cell fails to recognize the correct MHC molecule it is deleted, which is a process known as positive selection. A second test the T-cell will undergo is negative selection to test for self-antigen recognition. The cell is presented with “self”, and if it recognizes “self” as an antigen the cell is deleted to prevent auto-reactivity from occurring. These selection processes play an important role in regulating the immune system, protecting from auto reactive cells, and helping to explain autoimmune disorders such as Glomerulonephritis.

Autoimmune disease is a type of immunopathology which involves the immune system failing this selection process by attacking these “self antigens” after maturation. A possible culprit for autoimmune disease could be that not all self-reactive cells were eliminated, or perhaps there was gene rearrangement of the T-cell receptor after the cell was put through negative selection and it left the thymus. According to David Wagner, Ph.D. “It has just been shown that RAG reactivation does occur in peripheral T cells, and that it occurs in a population of T cells that have been demonstrated to be Auto Aggressive” (7). The rearrangement of the T-cell receptor after it leaves the Thymus would allow the cells to be free from positive and negative selection allowing the cell to recognize self antigen.

In the case of Glomerulonephritis one leading theory behind the cause of the disease is that it is due to the presence of a previous infection or a medical condition. Bryan Bunch, Ph.D. author of “Glomerulonephritis” lists the following plausible existing conditions that may result in the occurrence of Glomerulonephritis, “urinary tract infection, allergic reaction to drugs, sickle-cell anemia” (21-22). Robert Summerville, Ph.D. author of The Medical Advisor adds that other conditions such as “atherosclerosis, lupus, long term exposure to toxic chemicals or illegal drugs and some sexually transmitted diseases such as HIV and hepatitis can result in the occurrence of Glomerulonephritis” (530-533). The disease may occur after the onset of almost any medical condition that results in a sudden or dramatic reduction in blood supply to the kidneys. The loss of blood supply to the kidneys will cause kidney damage in which the damaged cells of the kidneys will exhibit MHC I molecules loaded with self antigen; which is presented to CD8+ killer T-cells. The damaged kidney cells become a target, which can transfer into the immune system targeting healthy cells as well as damaged cells.

In this theory in which CD8+ killer T-cells recognize MHC I molecules loaded with damaged self antigen, the Glomerulonephritis disease is associated with inflammation in the membrane of the kidneys where the immune system is attacking it, signifying a break in self-tolerance. According to Karen Newell, Ph.D. “Proteins that are not normally produced by the cell or that are, in some way, abnormal, undergo a process known as ubiquination […]. Ubiquinated proteins are then […] loaded into newly synthesized MHC class I molecules and are transported to the cell surface” (19). The MHC I/Peptide complex is recognized by a CD8+ T-cell, which after a CD4+ dependent CD8+ activation, the immune system begins to attack the kidney membrane.
When CD8+ killer T-cells mount an attack on infected or damaged cells, they induce cell death by a process of necrosis. According to Karen Newell, Ph.D., “Necrosis occurs when cells blow up or lyse in response to irreversible injury of some form. In this case, the release of the cellular contents is unrestrained by smaller subcellular organelles and release of the cytosolic contents can readily promote inflammation” (22). Inflammation persists causing an inflammatory cascade. If the inflammation cannot become regulated, the CD8+ killer T-cells will continue to attack the kidney membrane, even if the cells are healthy. Referring back to DNA recombination after mature T-cells leave the Thymus, the CD8+ T-cell receptor can also become rearranged by the re-initiation of RAG 1 and RAG 2, and if the TCR rearrangement recognizes healthy kidney membrane cells, it can continue to attack.

After mounting an attack, the adaptive immune system can develop memory to the self antigen, or kidney membrane. Mayer adds,” The adaptive immune system demonstrates immunological memory. It ‘remembers’ that it has encountered an invading organism and reacts more rapidly on subsequent exposure to the same organism” (1). In this case, the immune system has mounted a response to the self antigen and it has created “memory” to the kidney membrane. The immune system is constantly exposed to the organ so that it continues to mount a response in the presence of the kidneys in the body and this creates a chronic and recurring ailment.
The treatment of Glomerulonephritis consists of utilizing immunosuppressive drugs and corticoid steroids to alleviate inflammation. Many times if there is an underlying condition, the medication can temporarily mask the problem, but the disease can get progressively worse. The cause for Glomerulonephritis is highly debated and there are little definite answers to the immune system’s role in the disease. Methods and theories can be formulated, but without knowing the cause of the disease, creating a mistake-proof treatment and cure is difficult.




Works Cited
Bunch, Bryan, Ph.D. “Glomerulonephritis.” Diseases. 1997.
Mayer, Gene. Ph.D. "Immunology: Innate (Non-Specific) Immunity." Microbiology and
Immunology On-line. 2009. University of South Carolina School of Medicine. 11 May 2009 <http:>.
Newell, Karen, Ph.D., Intro to Immunology. 2nd ed.. South Lake, TX: Fountain Head Press,
2008.
Sadjadi, Seyed-Ali. M.D. "Glomerulonephritis (Nephritic syndrome)." The MERCK Manuals:
Online Medical Library 2007 1-6. 11 May 2009 <http:>
Somerville, Robert. Ph.D. The Medical Advisor. Alexandria: Time Life, 1996.
Wagner, David. Ph.D. “T Cells”. 2009.

Works Consulted
Newell, Karen. Ph.D. Class Lecture. Immunology. University of Colorado, Colorado Springs,
Colorado. Spring 2009.
Wagner, David. Ph.D. Class Lecture. Immunology. University of Colorado, Colorado Springs,
Colorado. Spring 2009.