Basic Science Flashcards
Tolerance
Failure of the immune system to respond in an aggressive way (meaning, not attacking self)
Where does early tolerance occur (central tolerance)
In the bone marrow and thymus. Most B and T cells die before becoming self-reactive
Negative selection
Process of controlling auto reactive cells. B cells express IgM on their surface and BCR recognizes this within the bone marrow which triggers their apoptotic death
How else does negative selection occur
Binding of an MHC complex and TCRs (CD4 and CD8) also causes apoptotic death
Peripheral tolerance
Process of controlling autoreactive cells as they exit the bone marrow or thymus. Via anergy or suppression.
T cell responses are….
Cell-mediated
What are the 2 classes of T cells
Cytotoxic and helper T cells
How can you classify T cells
Based on the presence of CD4 and CD8 proteins on their plasma membranes
What protein do cytotoxic T cells have on their membrane
CD8
What protein do helper T cells have on their membrane
CD4
What are cytotoxic T cells (CD8) good in fighting off
Bodies own cells that have become cancerous or are infected with virus (or some bacteria that resides in a host cell)
How do cytotoxic T cells work
“Attack” cells. Bind to target (antigen) and directly kill them via secreted chemicals. These cells see CYTOSOL derived peptides on an MHC I cell and kill it.
What is the role of helper T cells (CD4)
They activate B cells, macrophages and cytotoxic T cells (via secretion of cytokines). Bind with MHC II cells
How do helper T cells work with B cells
- B cells are bound to an antigen.
- They then present this antigen to a helper T cell (helper T cell also bound to an antigen to be activated)
- T cell then makes contact with the B cell via BCRs which induces B-cell activation (and thus antibody secretion). Cytokines play a big role in this activation
Of note: Dendritic cell packages the antigen and presents it to the helper T cell (all going on at the same time as the B cell/antigen interaction)
How do helper T cells activate cytotoxic T cells
- Activated helper T cell first helps other cells (i.e. dendritic cells)
- These dendritic cells then activate cytotoxic T cells
Basically the CD4 cell in this case indirectly helps the cytotoxic T cell via dendritic cells
How do helper T cells activate macrophages and neutrophils
Via different types of cytokine secretion
What is the difference between T cell receptors and B cell receptors
- T cell receptors remain on the T cell membrane where as antibodies are secreted.
- T cell receptor cannot combine with an antigen unless the antigen is complexed with plasma membrane proteins
What does the T cell receptor bind with
Both the antigen complex and the body protein
What does MHC stand for
major histocompatibility complex
What is the MHC
A group of proteins that come from the plasma membrane of a cell that must be complexed with the antigen in order for T cell recognition to occur
What are the 2 classes of MHC proteins
I - CD8 (cytotoxic)
II - CD4 (helper)
Where are class 1 MHC proteins found
All cells except RBC
Where are class 2 MHC proteins found
Mainly on the surface of macrophages, B cells and dendritic cells
MHC + antigen(once packaged in cell) =
Antigen presenting cells (APCs)
How do T cells detect antigens
They detect them when they are bound to an MHC
Macrophages, B cells and dendritic cells are APCs for what T cell
Helper T cell (CD4)
Helper T cells are the link between
Innate and adaptive immunity
What does a macrophage do to the antigen
It eats it, breaks it down into peptide fragments. These fragments then bind with class II MHC proteins and present the whole complex to the cell surface. Once there the helper T cell can then bind.
Epitopes
The peptide fragments of the antigen
Where do the “antigens” for CD8 cells come from when making the MHC/antigen complex
From within body cells (aka, protein fragments from a virus, or oncogene fragments. These fragments then join the MHC and are recognized by the cytotoxic cells. Cytosolic peptides
Central tolerance
Early in life
When B/T cells bind self-epitopes (antigens) they then undergo apoptosis
This means that self-reactive cells die before entering circulation
What is anergy
A peripheral tolerance mechanism. Occurs when the lymphocytes are unresponsive after binding an antigen or to an MHC complex. Basically T cells don’t receive 2nd signal they need
What is suppression
A peripheral tolerance mechanism. Occurs when regulatory cells (mostly T cells) inhibit the activity of other cells
Molecular mimicry
The antigenic agents (bacteria) may be similar enough to self molecules which stimulates a cross-reactive B/T cell response. The B/T cells then attack both the antigen and the host cells because they look the same
What is a clinical example of molecular mimicry
Diabetes, ankylosing spondylitis (klebsiella exposure), myasthenia gravis
Epitope spreading
The development of immune response secondary to an initial epitope. The initial epitope signals a second epitope which is the one that causes the autoimmune response
What is a clinical example of epitope spreading
Systemic lupus, Chrons, MS, pemphigus vulgaris, type I diabetes
Loss of suppression
Suppressor cells maintain peripheral tolerance but as we age the #’s of these cells declines which increase the risk that previous suppressed autoreactive cells will become active.
What is a clinical example of loss of suppression
Systemic lupus erythematosus (SLE)
Sequestered antigens
Some self molecules are hidden but may become exposed as a result of injury. Immune system may view them as foreign and attack. A big example of this is spermatogonia
What is a clinical example of sequestered antigens
Rheumatoid arthritis
Neoantigens
Self antigens that have been modified by some extrinsic factor (reactive chemicals) and appear “foreign” to the immune system
What is unique of neoantigens
Usually the removal of the agent responsible for the reaction stops the autoimmunity response
What are the most 2 common hypersensitivity reactions associated with humoral autoimmune disease
type II and III (also these patients have little ability to mount an antibody response
What are examples of humoral associated autoimmune disease
- Goodpasture syndrome
- Hashimoto thyroiditis
- Rheumatic fever
- Rheumatoid arthritis
- Systemic lupus erythematosus
What hypersensitivity reaction is associated with cell-mediated autoimmune disease
type IV
What are some examples of cell-mediated autoimmune disease
- MS
- Type I diabetes
- Rheumatoid arthritis
Relationship of HLA genes and autoimmune disease
Some HLA (aka MHC) genes are responsible for multiple autoimmune disease
Relative risk
The strength of an association between a particular HLA and an autoimmune disease. Compares the frequency of disease to those that carry HLA gene
What role do T cells play in graft rejection
MHC II molecules on macrophages destroy the new tissue because it does not recognize it
What are the main cells that HIV enters and why is this important
Helper T cells (CD4), dendritic cells and macrophages. Easily enters these cells because of one of the receptors on the T cell binds with a surface protein on HIV. This then binds the virus and the virus can enter cell and cause damage
How does HIV kill helper T cells (CD4) cells
Once inside the cell, the virus uses the hosts mechanisms to replicate, and eventually discards (kills) the cell when it is done with it. Also indirectly kills it because of normal immune functions
How does HIV develop into AIDS
The virus kills infected and uninfected helper T cells (CD4). By killing off T cells, eventually B and cytotoxic T cells won’t work as well which leads to higher susceptibility of infections and disease
How long does it usually take to go from HIV to AIDS
10years if untreated
What is primary immunodeficiency
Conditions that are caused by intrinsic (genetic) defect in the immune system. Less severe are treated with observation where as severe cases may warrant life long antibody replacement therapy or bone marrow transplant.
What are the 4 categories (classifications) of primary immunodeficiencies
- Combined cellular and antibody deficiency -15%
- Humoral deficiency - 65%
- Cell-mediated deficiency - 5%
- Phagocytic cell disorders - 10%
What is secondary immunodeficiency
Acquired. Occurs when the immune system is compromised due to an outside exposure (environmental factor).
Examples of secondary immunodeficiency
HIV, chemotherapy, burns, malnutrition
B-cell (humoral) deficiency
Occurs when there is an intrinsic B cell defect (no antibody production) or when T cell help is insufficient.
EX: x-linked agammaglobulinemia
Cellular immunodeficiency (T-cell mediated)
- Occurs when there is decrease in # and function of T cells. This can also have an affect on B cells and reduce their functionality as well (need cytokines for B cell proliferation).
- Often occurs along the IL12/IFN y axis. Which results in defective macrophages = inflammation and survival of antigen
Combined immunodeficiency
Occurs when both the antibody and cell mediated pathways are affect. Much more serious than if just one system acting alone. SCID
Phagocyte defects (immunodeficiency)
Occur when there is a defect in the #, function or both in phagocytes, neutrophils and NK cells
What is the most common immune deficiency disease
Selective IgA deficiency
What are commonly transplanted organs
- Kidney
- Liver
- Heart
Susceptible to opportunistic infections
What drug is given to transplant patients
Cyclosporins, bone marrow transplants, irradiation
3 types of tissue rejection
- Hyperacute rejection
- Acute rejection
- Chronic rejection
What are hyperacute tissue rejections caused by
Pre-exisiting antibodies, should not happen! Failure to establish vascular connection
What are acute tissue rejections caused by
T cells attack endothelium of the graft usually about a week post transplant. Host MHC will look wrong, this will cause an attack. Occurs between 2-4weeks. Donor and recipient differ at MHC genes.
What are chronic tissue rejections caused by
T cells activate macrophages which causes inflammation in arteries within the graft. Eventually the graft runs out of blood flow. Long process. Donor and recipient differ only by non-MHC genes
