49 Lymphatic Homeostasis
The proper functioning of body cells depends on precise regulation of the composition of the interstitial fluid surrounding them. The composition of interstitial fluid changes as substances move back and forth between it and blood and lymph. In addition, some disruptions come from the external environment. Fortunately, the body has mechanisms to try to inhibit foreign substances from entering the internal environment of the body and if they do get in, immune responses help to remove or neutralize the invader before the disruption leads to disease. Unfortunately, some factors or situations affecting the lymphatic system and immune responses could disrupt homeostasis.
Inflammatory Response and Clinical Disruptions to Homeostasis
Lymph Nodes
Lymph nodes play key roles in the body’s immune function. Lymph nodes filter harmful bacteria and other pathogens from the lymph, preventing them from reaching the blood and circulating throughout the body.
Sometimes, however, the lymph nodes and appendix become overwhelmed by these tasks, resulting in homeostatic imbalance. Lymph nodes can become swollen and tender as the pathogen they are designed to fight infect them and result in inflammation. This is a common symptom of many illnesses, and is often (incorrectly) referred to as having “swollen glands.” Swollen lymph nodes often occur behind the ears, on the neck, near the jaw or chin, and in the armpits. Colds, the flu, tonsillitis, ear infections, and mononucleosis are common causes of this swelling. Although pain and tenderness associated with swollen lymph nodes typically diminishes within a few days of onset, the swelling can last for several weeks after the onset of infection. After the infection has been eradicated from the body, the lymph nodes return to their normal size.
Appendix
The lymph tissue of the appendix helps control microbes in the colon from moving into the small intestine. Both of these structures activate the immune system to mount an attack against these pathogens.
Acute inflammation of the appendix, termed appendicitis, can be preceded by a number of possible causes. It is characterized by pain, high fever, and increased white blood count. The infection results in edema and ischemia and my progress to gangrene and perforation within 24 hours. Removal of the appendix may be recommended.
Ruptured Spleen
Homeostatic imbalances can also afflict the spleen, another lymph organ. Although the ribs protect the spleen from trauma, direct blows to the left upper abdominal area or even severe infection can result in rupture. When this happens, the spleen spills blood into the peritoneal cavity. As a result, it has been customary for such injuries to result in splenectomy, or total removal of the spleen to prevent excessive blood loss or further infection. In recent years, however, it has been found that the spleen has a significant capacity for self-repair. As a result, splenectomies have become less common, as doctors elect to leave part or all of damaged spleens in patients in the hopes the tissue will repair itself. In severe cases, when the spleen has completely ruptured and/or there is a high risk of infection, the spleen is still removed. The liver and bone marrow take over many of the spleen’s functions, although immune responses may be less robust in individuals without spleens.
Graft Versus Host Disease and Transplant Rejection
A bone marrow transplant is a procedure in which damaged or destroyed bone marrow (the soft, flexible tissue inside bones) is replaced with healthy bone marrow stem cells from a donor. Bone marrow is important because it is where blood cells—including lymphocytes—are produced. When bone marrow stem cells becomes damaged, as a result of certain types of cancer, chemotherapy, aplastic anemia, or other diseases, a bone marrow transplant or stem cell transplant is needed so that the body can continue to produce blood cells.
Graft versus host disease (GVHD) occurs when a patient receives a stem cell or bone marrow transplant from someone who is not closely histocompatible. The transplanted material attacks the recipient’s body. As mentioned previously, bone marrow contains stem cells that produce white blood cells and other immune system cells. No two people, except identical twins, have the same tissue type. Therefore, each individual expresses unique proteins on their cells that are a unique subset of major histocompatability complex (MHC) proteins. These unique proteins help signal to the T and B cells that the cells are yours and should not be attacked and destroyed. When a person receives a bone marrow transplant, they are receiving some else’s immune cells. These cells may not recognize the host cells as their own. As a result, the new immune cells can attack the host cells, resulting in fever, weight loss, pain, rashes, and of primary concern, the patient becomes more vulnerable to infection. Immunosuppressant medication is typically given to patients in order to reduce the chances of GVHD developing. If GVHD does occur, it is treated with high doses of corticosteroids. GVHD occurs in about 30–40% of patients who receive donations from relatives, and 60–80% of patients for whom the donor is not a relative.
Transplant rejection is a process in which a transplanted organ or tissue is attacked by the recipient’s immune system. For example, a person receiving a new kidney will require immunosuppressant drugs to prevent their immune cells from attacking and destroying the new, foreign kidney. Transplant rejection can be lessened by determining the MHC similarities between the donor tissue and the transplant recipient and trying to match them as closely as possible. Rejection is a cellular immune response via cytotoxic T cells inducing lysis of transplanted cells as well as an antibody mediated response via activated B cells secreting antibodies. The actions of the adaptive immune responses are joined by components of innate immune responses via phagocytes and soluble immune proteins.
Imbalances of Immune Function
Autoimmune Disorders
Finally, homeostatic imbalance can occur if the immune system fails to distinguish self from non-self, resulting in attack on self-cells and organs by auto-antibodies and self-reactive T cells. Autoimmune disease appears to be caused by failure of the tolerance processes to protect the host from the action of self-reactive lymphocytes. In an organ specific autoimmune disease, the immune response is directed to an epitope unique to a single organ or gland. Hashimoto’s thyroiditis, insulin-dependent diabetes mellitus (pancreas), myasthenia gravis (acetycholine receptors on muscles) and Crohn’s disease (GI) are examples of organ specific autoimmune diseases. Autoimmune diseases can also be directed toward a broad range of epitopes and involve a number of organs and tissues. Systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis are examples of systemic autoimmune diseases. A variety of mechanisms have been proposed for induction of autoimmunity and evidence exists for each of these mechanisms. Indeed there may be different pathways leading to autoimmune reactions. Current treatments include immunosuppressive drugs, thymectomy and plasmapheresis for diseases involving immune complexes. Also, blockers of some cytokines show success in several autoimmune diseases.
Systemic Lupus Erythematosus (SLE), or lupus, is an autoimmune disease that results from an improper immune cell balance. It is a chronic inflammatory immune disorder that results from an increase in a subset of helper T cells, and an improper activation of B cells and macrophages. This results in the activation of B cells that produce antibodies targeting the nucleic acids in the cells of several organs in the body. Depending on the B cells that are activated, many different locations can be affected including the brain, digestive tract, heart, lung, skin, or kidneys. Arthritis in the joints is a common symptom on patients with SLE.
SLE is more prevalent in women than in men. Symptoms can arise between the ages 10 to 50 and range in severity. Depending on the affected organ, symptoms can include chest pain, headache, migraine, fever, fatigue, vomiting, arrhythmias, malaise, hair loss, mouth sores, and the characteristic butterfly skin rash. This rash occurs in about 50% of all cases. The cause (etiology) of SLE is still unknown and an active area of research. There is no cure for SLE, but in most patients the disease can be managed and outcome (prognosis) for patients has been improving over the years.
Acquired Immunodeficiency Syndrome (AIDS) is caused by the retrovirus, human immunodeficiency virus (HIV). HIV infects T cells, specifically the T helper 2 subset (Th2) of T cells, in the human host. These Th2 cells are also called CD4+ cells because of the presence of the CD4 protein on its surface. Once inside the cell, HIV hijacks the host transcriptional machinery to replicate the virus nucleic acids. After the nucleic acids have been replicated the synthesis of virus proteins can occur. These newly synthesized viruses exit the cell and infect another T cell. In the process, HIV destroys the CD4+ cells in the body. By removing this population of immune cells, the immune system of an infected person can no longer function properly. Recall that the cytokines secreted by activated CD4+ helper T cells provide the second signal for activation of cytotoxic T cells and also enhances activation and proliferation of B cells and natural killer cells. Over time, as the CD4+ T cell population drops, other viruses, bacteria, or fungi take advantage of the weakened immune system and can gain access and proliferate in the host. Therefore, people infected with HIV will commonly also be infected with herpes simplex virus, pneumocystic pneumonia, tuberculosis, Candida, and more. Certain cancers, including Karposi’s sarcoma and lymphomas involving the B cells of the lymphatic system, are more prevalent in HIV infected patients. These co-afflictions contribute to illness and further damages the immune system of the patient. When the CD4 subset becomes very low, wasting syndrome, AIDS dementia, and other diseases that destroy the organs develop. While there is no cure for AIDS, medications to manage the disease exist. These long-term medications have greatly decreased the short-term mortality rate by maintaining CD4 cell counts, and patients with HIV are able to live much longer and more productive life.
Lymphoma
There are many types of cancer that affect either T or B cells. These are collectively called lymphomas. More than 30 types of lymphomas have been detected. Some are aggressive and fast-growing lymphomas, while others are less aggressive and slow growing. Lymphomas can arise at any age and occur within the germinal centers of lymph organs and nodes. Chromosomal changes can occur during any stage of development of the T or B cells. The most common form of lymphoma is the diffuse large B cell lymphoma (DLBCL). There are actually three subtypes of DLBCL, depending of the stage of development of chromosomal changes. DLBCL is an aggressive, fast-growing lymphoma that occurs in 30-40% of all lymphoma patients. In DLBCL, B cells continuously proliferate and do not undergo apoptosis. Chemotherapy is available to treat this disease.
Follicular lymphoma occurs in 20% of lymphoma patients. B cells in different stages of development undergo chromosomal changes leading to their uncontrolled growth. Unlike DLBCL, follicular lymphoma is a slow growing, non-aggressive cancer. Patients can live for a few years to greater than 20 years with this disease. Specific chromosomal changes occur in follicular lymphoma, and therefore it is detectable by a molecular test.
Mantle cell lymphoma is the least common lymphoma, occurring in approximately 5% of cases. Unlike the DLBCL and follicular lymphomas that arise from the cells in the germinal center, mantle cell lymphomas arise from cells in the mantle region of the node. Mantle cell lymphoma displays alterations in the cell cycle that controls the progression of the cell through replication and division. Mantle cell lymphoma is an aggressive disease. Patient survival generally is only 2–5 years.
Leukemia
Most people who hear the word leukemia consider it an ominous word. It means “white blood,” a term coined by one of the fathers of oncology, Rudolf Virchow, in 1847. Over the past two centuries, research has shown cancer to have many types with many different outcomes. Leukemia itself has many varieties depending on the cell type that proliferates (divides) abnormally, from acute aggressive to chronic, slowly developing types.
B-cell chronic lymphocytic leukemia is the most common form of leukemia. It affects B cell lymphocytes, which are produced in the bone marrow and develop in lymph nodes. Their primary function is to fight infections by producing a variety of antibodies. In this form of leukemia, abnormal B cells begin to grow out of control and accumulate – effectively crowding out healthy blood cells.
Leukemia patients have a tendency to suffer from repeated infections. During infections, microorganisms such as bacteria, viruses, fungi, or parasites penetrate the body’s defenses causing diseases. When healthy, the immune system is remarkably efficient keeping invaders at bay.
Allergy
Allergy or hypersensitivity reaction is an immune reaction to agents that are not normally harmful. These could be substances like strawberries, pollen, cat dander, or cockroach casings. Immediate hypersensitivities are allergic reactions that require prior exposure to the antigen. In this first exposure helper T cells produce IL-4, which drives the plasma cells to produce antibodies of the IgE isotype. The IgE binds to receptors present of mast cells for this isotype. Once enough IgE antibodies are present on mast cells, exposure to the same antigen induces mast cells to respond with an inflammatory response that releases histamine, a chemical that increases the dilation of the lymph and blood vessels. In addition, histamine produces watery eyes, itchy nose, and cough. Delayed hypersensitivities take hours to days to develop and are caused by T cells. The most common types result from contact of a substance with the skin or mucous membranes. For example, poison ivy, soaps, and drugs can cause a delayed hypersensitivity reaction. The substance is absorbed by the epithelial cells, which are then destroyed by T cells. The inflammation and tissue destruction causes intense itching.
