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Autoimmunity: Dr. LePoole

Additional Immunology Flashcards





What is Autoimmunity (AI)?

What causes AI?

AI results when toleracne to self-Ags is broken and the immune system sees and reacts to the self-Ags.

What 2 areas of tolerance can incur AI?




1. Central Tolerance = Defined by lymphoids (T cells, B cells) recognizing and reacting to self Ags, in the thymus or bone marrow = Primary lymphoid organs.

           - Deleted if react to self Ag

           - Dependent of Ag density (Ag + MHC complex), TCR density, CD4 / CD8 co-receptor expression.


- B cell tolerance:

           - B cells that are reactive to self Ag = Edit BCR. Seen in transgenic mice experiment.



2. Peripheral Tolerance:

- Induce tolerance to Ags not seen in the thymus or serum. Need mechanisms to prevent autoreactivity of lymphocytes to self Ags after they leave the primary lymphoid organs.

          = Generated by lymphoids in the periphery / away from the primary lymphoid organs (BM and thymus).


What are 4  mechanisms that cause peripheral tolerance?


1. Ignorance:

         - Immune privelaged sites: areas that sheild Ags from the immune system, such as the testis = lymphocytes can't see Ags here.



2. Suppression:

        = lymphocytes unresponsive to an Ag as they're suppressed by tolerized cells such as Foxp3 Tregs.



3. Anergy:

          = Lymphocytes are missing a co-stimulatory factor (from a Th, or APC) to activate them against an Ag.



4. Split Tolerance:

         = When one part of the immune system is responsive to an Ag but another is not. Like reactive B cells in the presence / or absence of non reative T helper cells.





How is toleranced acheived in the thymus?


How are Tregs created?


Good pic to know.


Thymus = central tolerance



- Tregs = Intermediate affinity for Self-Ag = get Foxp3 upregulated!


What is the proposed mechanism of T cell tolernace in cancer, induced by MDSC?


- MDSC = Myeloid Derived Suppressor cells in the peripheral tissue.


1. Tumor induces the production of MDSC in the peripheral tissue


2. MDSCs move to the tumor site and peripheral organs.


3. In the peripheral organs: MDSCs have:

           - High arginase I

           - High ROS production


4. MDSC present Ags to T cells causing nitration of the TCRs and to CD8 on the T cell's surface.


5. Changes in the TCRs and CD8 = can't rbind to MHCs = tolerance to peripheral MHCs!

- Ultimately CD8+ T cells (CTLs) are rendered non-responsive to Ag stimulation and can't kill tumor cells!


What kind of MHC recognition can cause AI?


Intermediate MHC recognition. If these lymphocytes aren't deleted, or made anergic then they can potentially react with self-Ags.


Or, T cells that react intermediately should become Tregs, but if not, they can be self reactive.

In an autoimmune disease involving CTLs, what other type of genes do you expect to identify?



= Activates CTLs / CD8+ along with co-stimulatory factors and cytokines.

Why are different autoimmune diseases assoicated with AI?
- HLA molecules are MHCs which present Ags. If they present self Ags = AI!
What does an association with a class I MHC versus a class II MHC tell you about the type of immune response involved in the disease?

- MHC II = Extracellular pathogen = activates T helper cells which help to activate the adaptive immune system and Abs via lymphocytes = Th1 (macrophages) and Th2 (Abs) CD4+ T cells


- MHC I = intracellular infection = activates cyctoxic cells like CTLs = Cell Mediated Immunity (CMI)

What are 2 examples of a monogenic (single gene mutation) AI syndrome?

1. APS-1: AI Polyendocrine Syndrome Type 1


- An autosomal recessive mutation in AIRE

- AIRE = involved in self Ag presentation (peripheral self Ags) to developing thymocytes in the thymus (Use mTECs too...)



2. XPID: X-Linked polyendocrinopathy

- Mutated Foxp3 gene = loss of Tregs to stop / contol T cell reactions!

Suggest a mechanism by which an infection can contribute to AI...

A viral infection, as in Cong Rubella


- If a viral Ag is similar to a self-Ag, then the viral Ag can evade the immune system, or the immune system can destroy it and those that look like it = AI


- Mimic HSP = bad

        - Heat shock proteins present Ags to DCs and response to stress by breaking down unnecessary proteins and releasing ROS.

= Molecular mimicry!

What's Antigen mimicry?

Sequence similarities between an Ag and self peptides.


- Can result in cross-activation of AI B or T cells by pathogen derived T cells.


- Little difference (like 1 nucleotide) between some Ags and self Ags!


What's epitope spreading?



- When humoral AI spreads from one part or type of self Ag to another. 


- Recognizing and reacting to the C-terminus then reacting with the N-terminus of a self Ag. Usually by Abs (Humoral AI or Type 2 (Th2) AI)


= Spread AI


= Self renewing AI as the reactions against self tissues occur, sequestered self Ags are released for the AI lymphocytes to continue to react with.


What's an example of systemic AI? What does it commonly react with?


- What's the cycle of systemic AI?

8 steps...


- Systemic AI usually reacts with global peptides, like histones and DNA and Topoisomerase...


Lupus as an example...




T cells: orange; B cells: red.

a | T cells are sensitive to lower thresholds of peptide activation.

- Co stimulatory molecule mutation

- Tissue damage is enough to start the reaction for AI

b | T cells provide stimulation to genetically hyper-responsive B cells.

c | Autoreactive B cells undergo somatic hypermutation and affinity maturation.

d | Pathogenic autoantibodies induce tissue damage and release of self-antigen,

g | therefore leading to a positive-feedback cycle.

e,f | self-antigen is presented by B cells in a second round of T-cell activation,

h | Autoimmune responses diversify; epitope spreading.

i | Activated T cells can also directly cause tissue pathology

What's organ specific AI, humoral?

- Organ specific AI causes a humoral response to a specific organ.

             - Preipheral tolerance may have fialed...


- IgG reacting to self. Common in blistering disorders = react to cell-cell adhesion molecules, Cell-ECM adhesion molecules: like desmoglein in Pemphegus.


What's organ specific AI, T and B cells?

T and / or B cells attack a specific organ.


- Autoimmune Thyroiditis:


1. Grave's Disease = Hyperthyroidism = Increase in TSH (Thyroid stimulating Hormone)

- By thyroid autoantibodies reacting with the thyroid receptor to increase TSH expression!


2. Hashimoto's disease = Hypothyroidism = Decrease in TSH

= T and B cells destroy the thyroid tissue

An example for T cell mediated, organ specific AI.



- Increase in T cells (CD4 / Th and CD8 / CTLs) react with melanocytes causeing de-pigmentation.

What are 2 models for AI and how are they produced?

1. Spontaneous model:

- In animals, a line breed to have an AI.


2. Inducible model:

- T cells can induce AI!!!

- AI reactivity can be transferred by T cells!


- Example of Myelin Basic Protein (MBP) + Adjuvant to induce MS in rats:

            = MBP specific T cells can induce EAE / MS in rats via transfer of T cells:



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