Immunologic Tolerance & Autoimmunity Flashcards
Immunological tolerance (IT) is specific unresponsiveness to an ________.
Antigen (Ag)
This is the term for when all individuals are tolerant to self-Ags.
Self-tolerance
The negative selection of self-reactive T lymphocytes in the thymus is NOT perfect. There is a low level of physiological _______-_______ that is crucial to normal immune function. The challenge is to understand how it becomes a pathologic process and how T cells and B cells recognize self and contribute to tissue injury.
Auto-Reactivity
Unlike “nonspecific” immunosuppression, _______ is Ag specific.
Tolerance
Central tolerance is induced in immature self-reactive lymphocytes in the _________ lymphoid organs.
Primary
Central tolerance ensures that mature lymphocytes are NOT REACTIVE to self _____.
Ags
________ tolerance is induced in mature self-reactive lymphocytes in peripheral sites. It is needed to prevent activation of these potentially dangerous lymphocytes in the tissues.
Peripheral
With this type of tolerance, immature lymphocytes specific for self Ags may encounter these Ags in the generative lymphoid organs and are either:
- deleted
- change BCR specificity (B cells only)
- develop into Treg cells
Central tolerance
With this type of tolerance, mature self-reactive lymphocytes in peripheral tissues may be either:
- inactivated (anergy)
- deleted (apoptosis)
- suppressed by the Treg cells
Peripheral tolerance
The _______ also has a special mechanism for expressing many protein Ags that are present only in certain peripheral tissues.
Thymus
TCR signaling in immature T cells triggers mitochondrial pathway of apoptosis – _______ _______.
Negative selection
Recognition of self Ags by immature T cells in the thymus leads to:
1) The _______ of the cells by negative selection
(OR)
2) The development of ______ cells that enter peripheral tissues
Death
Treg
Central tolerance takes place in the thymus. Thymocytes undergo a maturation and selection process. Nonfunctional thymocytes showing no affinity at all undergo _________.
Apoptosis
Strongly self-reactive thymocytes – as determined by interactions with _____-self peptide complexes – are also deleted.
MHC
Only thymocytes that are activated by MHC-self peptide complexes below a certain threshold are ________ selected and migrate into the periphery as mature T cells.
Positively
T/F. Most of these thymic emigrants develop into effector CD4+ and CD8+ T cells, and mediate both cell-mediated and humoral (Ab-mediated) immune responses.
True
A small percentage of T cells that emigrate from the thymus express ______ and develop into natural CD4+ CD25+ CTLA4+ Treg cells.
FOXP3
Immature B cells that recognize self Ags in the bone marrow with high avidity die by apoptosis or undergo receptor editing and change the specificity of their ______.
BCRs
This is the term for further rearrangement and replacement of the IgL-chain genes that occurs until non-self-recognizing receptors are produced or the cell dies.
Receptor editing
Weak recognition of self Ags in the bone marrow may lead to _______ (functional inactivation) of the B cells.
Anergy
_______ _______ and anergy were major mechanisms mediating central tolerance of developing autoreactive B cells, resulting in the elimination of autoreactive clones, and preventing immune responses against self.
Clonal deletion
______ regulates expression and helps to eliminate T cells that are reactive to normal, healthy proteins.
AIRE
When an immature B cell reacts with a self-antigen with high _______, such as a highly expressed membrane-bound protein, it undergoes apoptosis within 2-3 days.
Avidity
Low _______ interactions of B cells with self-antigens induce unresponsiveness to subsequent stimulation or anergy but allowed for migration into peripheral compartment. The anergic B cells fail to enter follicle and have reduced life-span.
Avidity
Clonal deletion and anergy are not the only modes of selection against autoreactive immature B cells, but there operates another system, namely, ______ ______.
Receptor editing
Autoreactive immature B cells reactivated their Ig gene rearrangement program at the Ig light chain loci resulting in the expression of a new light chain that paired with the existing H chain to form a non-autoreactive _____, and event that promoted the selection of these edited B cells into the periphery.
BCR
The kappa/lambda ratio in the peripheral B cells is estimated to be ______.
3:2
T/F. Precursor (pre)-B cells, which already express rearranged IgH chains recombine the locus that encodes IgL chain, yielding a lymphocyte with an autoreactive antigen receptor. BCR signaling promotes developmental arrest and continued recombination.
True
Receptor editing of the IgL chain leads to expression of a distinct IgL chain, generating cell-surface _________ that lacks self-reactivity.
Immunoglobulin
______ cells are key mediators of peripheral tolerance.
Treg
Treg cells may inhibit T cell activation by ______ and inhibit T cell differentiation into ______.
APCs
CTLs
Treg cells may prevent T cells from providing help to _______ in the production of Abs.
B cells
_______ Treg cells can also be generated from peripheral T cells and they are called induced Treg cells (iTreg cells).
FOXP3+
In addition to the natural Treg cells which differentiate in the thymus, mature T cells outside the thymus can also acquire Treg phenotype and function. These are called…
Induced Treg cells (iTreg cells)
FoxP3 can be induced in naive CD4+ cells in vitro by antigen recognition in the presence of ______.
TGF-B
There is a close developmental relationship between iTregs and ______ cells.
Th17
Ag recognition in the presence of TGF-B induces FoxP3 expression if ____ is not present. In contrast, Ag recognition in the presence of TGF-B + ______ prevents FoxP3 expression, induces expression of the retinoic acid receptor (RAR) related orphan nuclear receptor RORyt expression and therefore, Th17 cell differentiation.
IL-6
IL-6
The development and survival of these regulatory T cells (Treg) require ______ and ______.
IL-2
FoxP3
In peripheral tissues, Treg cells suppress the activation of ________ lymphocytes.
Self-reactive
(NATURAL/INDUCED) Treg cells are generated by self Ag recognition in the thymus.
Natural
(NATURAL/INDUCED) Treg cells are produced by Ag recognition in LNs and GI tract.
Induced
Mature _____ cells that recognize self Ag in peripheral tissues in the absence of specific Th cells may be rendered functionally unresponsive or die by apoptosis.
B cells
The CD22 inhibitory receptor is phosphorylated by Lyn and then recruits SHP-1 tyrosine phosphatase attenuating BCR signaling. Therefore, defects in Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and the CD22 inhibitory receptor lead to _________.
Autoimmunity
Peripheral tolerance is primarily found in splenic transitional B cells, which depends on tonic BCR signaling thresholds and survival signals from ______.
BAFF
The balance of ______ vs. ______ signaling controls the outcome of peripheral tolerance.
BCR
BAFF
Incomplete induction of central tolerance in the thymus (______ deficiency causes Autoimmune Polyendocrine Syndrome).
AIRE
Impaired production of regulatory T cells (_______ deficiency causes IPEX syndrome).
FoxP3
Decreased clearance and impaired tolerance induction by apoptotic cells (complement deficiency of _____ and _____).
C1q
C4
Altered immune signaling thresholds (_____ polymorphisms).
CTLA-4
The (POSITIVE/NEGATIVE) selection of T cells in the thymus is necessary for the maintenance of self tolerance.
Negative
Medullary thymic epithelial cells have a key function as ______. They express a large number of self-Ags that are presented to developing T cells.
APCs
Mutations in ______ protein cause a breakdown of central tolerance. This protein has been proposed to function as a transcription factor.
AIRE
Mutation in ______ is associated with decreased expression of self-Ags in the thymus.
AIRE
The AIRE regulates the expression of tissue-restricted Ags (TRAs). Peptides derived from these Ags are displayed on the Medullary Thymic Epithelial cells. Ags are then recognized by immature Ag-specific T cells, leading to the deletion of ______-______ T cells.
Self-reactive
In the absence of functional ______, these self-reactive T cells are not eliminated and they can enter tissues where the Ags continue to be produced and cause injury and autoimmunity.
AIRE
T cell responses are induced when (1) TCR recognizes an Ag presented by APC (signal 1) and (2) ______ recognize B7 costimulators on the APCs (signal 2).
CD28
If the T cell recognizes a self Ag without costimulation, the T cell becomes unresponsive to the Ag because of a block in signaling from the TCR complex. Blocking may be the result of:
– recruitment of ________ to the TCR complex
– activation of ________ ligases that degrade signaling proteins
– engagement of inhibitor receptors CTLA-4
***The anergic T cell remains viable but is unable to respond to the self Ag.
Phosphatases
Ubiquitin
When T cells recognize self Ags, they may engage inhibitory receptors of the ______ family, whose function is to terminate T cell responses. The best established inhibitory receptors are ______.
CD28
CTLA-4
Upon Ag encounter, individual populations of T cells undergo expansion and later contraction after the elimination of Ag. T cell activation is regulated by members of the _____-_____ family of costimulatory molecules.
B7-CD28
CTLA4 is homolog of ______ and is an inhibitory receptor.
CD28
_______ provides signals that terminate immune responses and maintain self-tolerance.
CTLA4
Uncontrolled lymphocyte activation with massively enlarged LNs and spleen and fatal multi-organ lymphocytic infiltrates is seen in CTLA4 KO mice. Blocking of CTLA4 with Abs also enhances ________ diseases in animal models.
Autoimmune
Polymorphisms in the ______ are associated with several autoimmune diseases in humans, including type 1 diabetes and Graves’ disease.
CTLA4
CTLA4 has two important properties:
– CTLA4 expression is low on resting T cells until the cells are activated by ______.
– Once expressed CTLA4, terminates continuing activation of these responding T cells.
Ag
CTLA4 is expressed on ________ T cells (Treg) and mediates the suppressive function of these cells by inhibiting the activation of naive T cells.
Regulatory
Engagement of _______ on a T cell may deliver inhibitory signals that terminate further activation of that cell.
CTLA4
CTLA4 on _____ cells or responding T cells binds to B7 molecules on APCs or makes unavailable to CD28 and blocking T cell activation.
Treg
________ Treg cells develop in the thymus and are positively selected in the thymus via strong TCR interactions with self-Ags. After recognition of self-Ags they are not eliminated by apoptosis.
Natural
________ Treg cells are able to produce anti-apoptotic molecules which protect them from negative selection in the thymus.
Natural
The generation of ________ Treg cells requires the TGF-B.
Inducible
All Treg cells express _______ transcriptional factor and are ______ ______ positive.
FOXP3
CD4+
CD25+
All Treg cells typically express high levels of CTLA4, and cytokine _____ is critical for survival and functional competence of all Treg cells.
IL-2
Treg cells are endogenous long-lived populations of ________ specific T cells.
Self-Ag
Treg cells serve to prevent potentially ________ reactions.
Autoimmune
IL-2 receptor alpha chain (IL-2Ra) is also called ______.
CD25
The immunoregulatory enzyme _______ suppresses T cell responses and promotes immune tolerance by mechanisms of tryptophan starvation.
IDO (indoleamine 2,3-dioxygenase)
______ inhibits the proliferation and effector functions of T cells.
TGF-B
TGF-B inhibits development of Th1 and Th2 subsets but promotes _____ in cooperation with IL-1 and IL-6.
Th17
TGF-B inhibits activation of M1 macrophages, and regulates the differentiation of induced _______ Treg cells.
FoxP3
TGF-B stimulates the production of _____ by inducing B cells to switch to this isotype.
IgA
_______ promotes tissue repair after local immune and inflammatory reactions subside, stimulating collagen synthesis and matrix-modifying enzyme production by macrophages and fibroblasts.
TGF-B
There is no fundamental difference between the structure of self auto-Ags and non-self Ags because Ags are all proteins composed by the same ______ ______.
Amino acids
Pathologic immune response against self Ags often clinically manifested as “immune-mediated inflammatory diseases”. Caused by the activation of T cells and/or B cells in the absence of an ongoing infection or other discernible cause. This is a result of a _________ immune system that causes one’s own immune system to attack the self.
Hypersensitive
T cells that are physically separated from their specific Ag cannot become activated, a process termed…
Immunologic ignorance
T cells that express the _____ (CD95) can receive their signals from cells that express ______ and undergo apoptosis, a process known as deletion.
Fas
FasL
_______ (CD152) that binds CD80 on APC and inhibits T cells activation.
CTLA4
Regulatory T cells can inhibit through the production of inhibitory cytokines such as ______ and ______.
IL-10
TGF-B
Environmental triggers, such as infections and other inflammatory stimuli, promote the influx of lymphocytes into tissues and the activation of self-reactive T cells, resulting in tissue ______.
Injury
Autoimmune diseases may be either ______ or ______ specific, depending on the distribution of the auto-Ag that are recognized.
Systemic
Organ
________ disease tend to be chronic, progressive, and self-perpetuating.
Autoimmune
Failure of the mechanisms of self-tolerance in T or B cells underlies cause of all ________ diseases.
Autoimmune
_________ or an initial innate immune response is the first step in autoimmunity development.
Inflammation
Most autoimmune diseases are complex ______ traits.
Polygenic
Affected individuals inherit multiple genetic _________ that contribute to disease susceptibility.
Polymorphisms
Among the genes that are associated with autoimmunity, the strongest associations are with ______ genes.
MHC
Polymorphisms in _______ genes is also associated with autoimmunity.
Non-HLA
Susceptibility genes act with _________ factors to cause the diseases.
Environmental
Rheumatic fever is triggered by streptococcal infection and mediated by cross-reactivity between streptococcal Ags and ______ ______.
Cardiac myosin
Multiple sclerosis – T cells react with _______ ______ ______ and peptides from Epstein-Barr virus, influenza virus type A, and human papilloma virus.
Myelin basic protein
_________ (bystander) activation: Microbial infection can also cause polyclonal activation of autoreactive lymphocytes due to massive activation of naive cells and release of cytokines (cytokine field).
Polyclonal
Microbes that kill cells can cause inflammation, the release of sequestered Ags (Ags that ARE NOT well presented in the _______ _______ organs) leading to autoimmunity.
Primary lymphoid
T/F. Autoimmune disease are much more common in men.
False. More common in women.
________ exacerbate Systemic Lupus Erythematosus (SLE) in mouse models of the disease by altering the B-cell repertoire in the absence of inflammation.
Estrogens
Drugs can also alter the immune repertoire: Penicillins and cephalosporins can bind to RBC membrane and generate a neoantigen that elicits an auto-Ag that causes ______ ______.
Hemolytic anemia
The blockade of TNF-a (ENBREL or other inhibitors) can induce antinuclear Abs and even SLE and Multiple Sclerosis (MS) in certain persons. TNF-a has inhibitory effects on activated T cells, but it remains unknown how TNF-a induces ________.
Autoimmunity
