Diabetes

There are two different types of diabetes. In type 1 diabetes the body's insulin production is highly impaired. The body's immune system for some reason, attacks and destroys the insulin-producing cells in the pancreas, which can ultimately lead to complete insulin deficiency. Why the immune system, which is responsible to defend the body against infection, attacks and destroys its own insulin-producing cells is not known. Many researchers believe that a combination of both genetic and environmental factor such as viruses or chemicals can cause immune system's auto-reactivities. Type 1 diabetes diagnosed normally in children and young people. Most of the patients, who suffer from type-1 diabetes do not have a close relative with type 1 diabetes. Patients are normally treated with insulin with some form of injections. (Picture from medical-look)

 The first signs are usually large amounts of urine, increased thirst, unusual tiredness and sometimes weight loss. The large volume of urine is because of high glucose (sugar) levels in the blood, which makes the kidneys to extract the glucose in the urine and the sugar draws water with it, which cause increased thirst. Fatigue and weight loss can also be other symptoms, which is due to serious disruptions in metabolism due to insulin deficiency. Unfortunately, the symptoms appear only when most of the insulin-producing cells are destroyed.

Type 2 diabetes is the most common form of diabetes (>80 %), in which the body either doesn't produce enough insulin or the cells don't respond to the insulin. Many people with type 2 diabetes are overweight and may produce much more insulin than normal level. The exposure of cells to high concentrations of insulin may lead to insulin resistance and thus diabetes. Both types of diabetes can have similar symptoms. Unlike type-1 diabetes, the type-2 diabetes is not an autoimmune disease and is diagnosed normally in people above 40 years of age.

Atherosclerosis

Atherosclerosis is an inflammatory disease in which plaque is made inside the arteries. These blood vessels are responsible for carrying oxygen-rich blood to the vital organs such as heart and other parts of the body. Gradually, growing and hardening of the plaque results in narrowing arteries, which in turn limits the flow of blood to the organs or tissues (Picture from Ohiohealth). Any artery can be affected by atherosclerosis. This can lead to different diseases such as heart attack or stroke causing serious problems and even death. Lack of physical activity, smoking and an unhealthy diet are among most important causes of atherosclerosis.

Immunology of atherosclerosis

It has now become clear that atherosclerosis is an immune system-mediated inflammatory disorder involving antibodies, components of the complement system, immune cells such as macrophages and lymphocytes infiltrating the walls of the arteries, by which participating in the formation of the plaques. Cytokines that regulate a broad range of inflammatory responses are also involved in the pathogenesis of atherosclerosis. In addition, chemokines, which are involved in recruitment of leukocytes to the site of inflammation have also been reported to play a role in atherosclerosis. It is believed that the inflammatory reactions are triggered by the damaged artery, caused by the oxidized low-density lipoprotein molecules. These molecules carry cholesterol throughout the body.

Psoriasis

Psoriasis and atopic eczema are the most common chronic inflammatory skin diseases affecting a large number of patients worldwide. Both diseases have a substantial negative impact on the patients' quality of life.

Psoriasis is a noncontagious, lifelong skin disease. According to the National Institutes of Health, as many as 7.5 million Americans have psoriasis. In Sweden around 3% of people suffer from psoriasis. It usually causes red scaly patches on the skin. The scaly patches caused by psoriasis, called psoriatic plaques, which are areas of inflammation and excessive skin production. Skin rapidly accumulates at the sites and has a silvery-white appearance. Plaques mainly occur on the skin of the elbows and knees, but can affect any area such as scalp and genitals.

Psoriasis can also cause inflammation of the joints, which is known as psoriatic arthritis. Up to 30 percent of people with psoriasis also develop psoriatic arthritis, which causes pain and swelling in and around the joints. Early diagnosis and treatment of psoriatic arthritis can considerably relieve pain and inflammation.

Immune system and psoriasis

In psoriasis immune cells antigen presenting cells such as DCs and also some T cells produce the key inflammatory molecules such as tumor necrosis factor (TNF), which plays a role in almost all psoriasis symptoms such as inflammation, redness, pain, and itching in the plaques. It can make blood vessels multiply, and white cells move from the blood vessels into the skin. This may explain why patients bleed so easily when they scratch the plaques. DCs can also produce and release the cytokine IL-23, which stimulates a group of CD4+ Th cells, Th17 cells, to produce the key pathogenic cytokines, IL-17 and IL-22, in the psoriatic lesions. In addition to the Th17 cells, antigen presenting cells-derived IL-12 can also mediate differentiation of CD4+ Th cells towards Th1 cells, which can produce TNF and IFN-gamma. All the mentioned cytokines have been shown to be involved in the pathogenesis of psoriasis. IL-17, IL-23 and IFN-gamma can activate the keratinocytes, and these cells in turn will release proinflammatory cytokines such as IL-8 and other factors, which play a role in inflammatory responses.

Conditional inactivation of a gene using a Cre/loxP inducible system

Creating KO mice is one of the best and advanced methods for studying the function of a gene in vivo. However, in a considerable number of cases, it has turned out to be problematic, as it can cause early embryonic lethality. Even though this is a clear indication for the importance of the candidate gene in the embryonic development, the real function of the gene in adults remains unanswered. Apart from this, inactivation of a gene in all tissues will make interpretation of the results very complicated, as it can not easily be concluded whether the phynotpe in a tissue is the consequence of gene inactivation in that particular tissue or it is due to inactivation of that gene in other tissues. To address these issues, a more advanced system has been created, by which a gene can conditionally be inactivated either in a particular cell types or in a specific time.

The Cre-loxP system has been widely used for inactivation of a gene in a particular tissue. In this system, the Cre recombinase mediates excision, recombination between loxP sites and consequently inactivation of a floxed gene or in other word a target gene flanked by two loxP sites. For creation of this system in mice two different lines of mice are required. First, a conventional transgenic mouse line expressing Cre recombinase protein in a specific tissue or cell type, and secondly a mouse line that carries a floxed gene. Crossing these two mouse lines creates a double transgenic line carrying the floxed gene and expressing the Cre protein. Expression of the cre is under the control a promoter, which directs the expression of this protein to a particular tissue or cell type. Thus, inactivation of the target gene occurs only in those cells expressing Cre. The main advantage of using this system is inactivation of a gene in a cell type-specific manner. However, similar to the conventional methods, the embryonic lethality can still be a problem.

The Cre/loxp inducible system is currently one of the most advanced tools for not only cell type-specific but also time-specific inactivation of a target gene. In this system Cre protein is fused to a mutated form of estrogen receptor (ER). In unstimulated cells Cre-ER is sequestered in the cytoplasm but after addition of the the drug Tamoxifen, which is a ligand for the mutated ER, the ER and Cre translocate to the nucleus, where Cre can excise and inactivate the gene in a particular time. See the attached film for more details.

The Age-Associated Thymic Involution

The thymus gland is the heart of the immune system, especially during its development. It is the main site for the development of T lymphocytes. These cells are more often called T cells. T cells play a central and crucial role in the immune system. Thymus is the site where bone marrow derived very immature T cells are developed, so that mature and competent T cells can be produced and exported via circulation to the peripheral lymphoid tissues such as lymph nodes or spleen to play their active role in the immune system. (Picture from the National Cancer Institute)

The thymus shrinks gradually by age, a process called the “age-associated thymic involution”. This process starts normally after puberty. Thymic involution results is a decreased number of thymocytes or in other word immature T cells in the thymus. This leads to production of less mature T cells. Thymic involution may also involved in Immunosenescence, which refers to the gradual deterioration of the immune system especially in aged people. This might contribute to higher susceptibility of aged people to cancer and infection.