Tolerance, autoimmunity, transplantation Flashcards
What is immunological tolerance?
Immunological tolerance is a complex series of mechanisms that impair the immune system to mount responses against self antigens. Central tolerance occurs when immature lymphocytes encounter self antigens in the primary lymphoid organs, and consequently they die or become unreactive.
How can immunological tolerance be breached?
Tolerance can be broken naturally (as in autoimmune diseases) or artificially (as shown in experimental animals, by x-irradiation, certain drug treatments and by exposure to cross reactive antigens).
What immunological responses and which components of the immune system are
involved in autoimmunity?
Major risk factors for autoimmunity
How are alloantigens from transplanted organs presented to the hosts T-cells?
Why do we say that allograft rejection follows the rules of immune specificity and
memory?
What are the causes/mechanisms of transplant rejection in MHC identical
transplantations?
What is graft versus host disease?
Tolerance
prevention of an immune response against self structures
Central Tolerance
deletion or inactivation of self-reactive lymphocytes before they mature
PLO
Primary lymphoid organs
Peripheral Tolerance
It takes place in the immune periphery (after T and B cells egress from primary lymphoid organs). Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.
Promotes peripheral tolerance:
Route or timing of exposure (Oral exposure/ Early in life)
* High dose antigen/ long term antigen exposure
* Low levels of costimulation
* Immature antigen presenting cells (APC)
Regulatory T cells (Treg )
are a specialized subpopulation of T cells that act to suppress immune response, thereby maintaining homeostasis and self-tolerance. It has been shown that Tregs are able to inhibit T cell proliferation and cytokine production and play a critical role in preventing autoimmunity.
Natural Treg, (tTreg )
– Peripheral (Induced) Treg
Immunophenotype:
– CD4+, CD25++, FoxP3+,CTLA-4
Autoimmunity
an aberration in the body’s normal development such that the immune system mounts an attack against its own cells. The etiology behind autoimmune diseases is multifactorial, with genetic, hormonal, and environmental factors all playing a role.
Autoantibodies
Againstreceptors:Inhibitoryorstimulating
– Otherantigens:inflammation
– Fcmediatedphagocytosis
– Fc activation of neutrophils ,eosinophils,basophils,mastcells
– Immuncomplex
- circulation og deposition
– Complement
Membran Attac complex
Graves disease
is an autoimmune disorder that can cause hyperthyroidism, or overactive thyroid. The thyroid is a small, butterfly-shaped gland in the front of your neck. Thyroid hormones control the way your body uses energy, so they affect nearly every organ in your body, even the way your heart beats.
Myastenia gravis
Myasthenia gravis is a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles (the muscles that connect to your bones and contract to allow body movement in the arms and legs, and allow for breathing).
Diabetes Mellitus
is the scientific name for diabetes, but it is more commonly known simply as diabetes. It’s when your body can’t produce enough of a hormone called insulin, or the insulin it produces isn’t effective. There are two main types of diabetes mellitus: type 1 and type 2.
Multiple Sclerosis – T helper cells activates the innate immune cells
is a condition that can affect the brain and spinal cord, causing a wide range of potential symptoms, including problems with vision, arm or leg movement, sensation or balance. It’s a lifelong condition that can sometimes cause serious disability, although it can occasionally be mild.
Experimental Autoimmune Encephalomyelitis (EAE) – a MS model
is an inflammatory, autoimmune demyelinating disease of the CNS in rodents, with pathologic and clinical similarities to human multiple sclerosis (MS).
Genetic factors associated with Autoimmunity
The proteins encoded by genes associated with autoimmune diseases are involved in several inflammatory mechanisms, such as antigen presentation, type I interferon, Toll-like receptor and NF-κB signaling, B-cell and T-cell function, apoptosis, and clearance of cellular debris and immune complexes
Epitope spreading
refers to the development of an immune response to epitopes distinct from, and noncross-reactive with, the disease-causing epitope. Diversification, or the ability of the immune system to attack multiple targets on a pathogen has obvious advantages.
Molecular mimicry
is defined as structural similarity between antigens coded by different genes. Molecular mimicry has long been implicated as a mechanism by which microbes can induce autoimmunity.
Transplantation
Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organs may be transported from a donor site to another location.
MHC compability
determines the success of transplantation
Rejection
Normal immune response against foreign antigens
* Cellular and humoral
* Adaptive and innate
* Primary and secondary
Hyperacute rejection
Occurs within minutes of the kidney transplant, when the recipient’s antibodies immediately recognize the kidney as foreign and attack it. Hyperacute rejection usually cannot be treated and results in the loss of the kidney.
reformedantibodies (ABO and HLA)
– Destruction of capillaries of the graft
Acute rejection
occurs days to months after a transplant when the immune system identifies a grafted organ as foreign and attacks it. Acute transplant rejection is common and the prognosis is guarded.
Tcells(CD4+&CD8+),APC, cytokines, and antibodies)
– Sensitization and later effector stage
Chronic rejection
is the leading cause of organ transplant failure. The organ slowly loses its function and symptoms start to appear. This type of rejection cannot be effectively treated with medicines. Some people may need another transplant.
Cellularandhumoral(including ADCC)
MHC matching
HLA-compatibility
– Depending on immunosuppression
* HLA-identical–monozygotictwins * HLA-haploidentical
* HLA-1sharedhaplotype
Bloodgroup matching
The blood type of the donor must be compatible with the recipient. The rules for blood type in transplantation are the same as they are for blood transfusion.
Cross-matching
A crossmatch test is a test that determines the immunologic risk of a recipient with a potential donor by ensuring that there are no transplant-relevant circulating antibodies in the recipient directed against donor antigens.
Graft vs Host-disease
In case of Hemaetopoietic stemcell transplantation
* Foreign immune cells are transplanted
* Mature allogenic T cells (Graft) attack Host cells
GvHD means the graft reacts against the host. The graft is the marrow or stem cells from the donor. The host is the person having the transplant. GvHD happens when particular types of white blood cell (T cells) in the donated stem cells or bone marrow attack your own body cells.
Pregnancy as an allograft
From an immunologic viewpoint, the fetus with its paternal antigens may be considered a successful allograft in the maternal host. Understanding the basis of this host-allograft relationship remains a fundamental unsolved problem in transplantation immunobiology.
Allograft
The transplant of an organ, tissue, or cells from one individual to another individual of the same species who is not an identical twin.
Immune suppression
Antiinflammatory
* Cytotoxic
* Inhibitproliferation
* Inhibit T cell signalling
* Blockingco-stimulation
* Depletionofimmunecells
Anti-inflammatory
or antiphlogistic is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics.
Corticosteroids
* anti-inflammatory drugs that alter the transcription of many genes
* Wide range of adverse effects
T cell signaling
It provides connection between T cell and the antigen-presenting cell (APC). TCRs activation promotes a number of signaling cascades that ultimately determine cell fate through regulating cytokine production, cell survival, proliferation, and differentiation.
Monoclonal antibodies
A type of protein that is made in the laboratory and can bind to certain targets in the body, such as antigens on the surface of cancer cells. There are many kinds of monoclonal antibodies, and each monoclonal antibody is made so that it binds to only one antigen.
