L1 - Autoimmunity and Immunologically-mediated disease

What principles are applicable in both immunopathology and normal immunity?

Specificity, diversity, discrimination of self and foreign, immunological memory, and termination of the response

What two principles between immunopathology and a normal immune response are different?

The discrimination between self and foreign and termination of the response

List some characteristics of the ideal immune response

Directed only against harmful immunogens, completely effective and eradicates the immunogens, and completely protective with no damage to host

List some characteristics of the actual immune response

Damage to host often results due to the etiologic agent, inflammatory/immune response, autoimmunity, and iatrogenic reactions

Damage due to an etiologic agent

The bacteria or virus causes damage to the host prior to development of immunity or due to a deficiency (the response wasn't fast enough)

Damage due to the inflammatory/immune response

The inflammatory response can cause damage if unregulated

Damage due to autoimmunity

The immune response is against self antigens

Damage due to iatrogenic reactions

Adverse reactions as a response to therapy to help clear harmful immunogens

Why is it not easy to distinguish between protective and immunologically-mediated diseases?

They are often part of the same process. Normal immune responses work just like abnormal ones, just the antigen is different.

We can classify an immunologically-mediated disease based on:

The source of the antigen, the mechanism of the immune response, and clinical aspects

Give the different classifications of immunologically-mediated diseases based on the source of the antigen

Autoimmunity, alloimmunity, and allergy

Give the different classifications of immunologically-mediated diseases based on the mechanism of the immune response

IgE-mediated, cytotoxic, immune complex, and cell mediated

Immunologically-mediated diseases based on the clinical aspects

It involves a mixture of the source of the antigen and the mechanism of the immune response. It also involves other aspects such as organ systems

What is tolerance?

Your immune system does not see your own cells as foreign invaders. Essentially that you don't reject yourself.

Is tolerance inherited or acquired?

Acquired

1 multiple choice option

When is tolerance most readily developed?

During fetal life

Reminder: Describe how the baby is determining self-recognition in the womb

The baby is in a sterile environment and assumes everything is "self". It will become tolerant to all antigens present

In order to develop tolerance, the host needs ________ presence of the immunogen

continuous

1 multiple choice option

Tolerance can be established as a clinical goal. Give some examples of this

Therapy of allergies and establishments of allographs

Give the two primary mechanisms of tolerance

Central tolerance and Peripheral tolerance

Describe how tolerance is developed in T cells through central tolerance

During T cell development, T cells undergo a double positive phase and are presented with self-immunogens. If they bind tightly to these immunogens, they are considered autoimmune and undergo negative selection via apoptosis

Describe how tolerance is developed in B cells through central tolerance

As B cells mature in the bone marrow, they start expressing IgM on their surface, which acts as their receptor. They are then exposed to self-immunogens. If they bind tightly to these immunogens, they are considered autoimmune and undergo negative selection.

Describe peripheral tolerance

Immunogen-induced anergy in absence of co-stimulation in B and T cells

Reminder: What does a T cell need in order to become fully activated?

Co-stimulation: this signal comes from the B7 region on the APC. This will bind to the CD28 receptor on the T Cell.

Reminder: What does it mean if a TCR recognizes a peptide bound to an APCs MHC molecule but there is no B7 presentation?

This means that the TCR is recognizing peptides that are considered self. They are autoimmune and become anergic

Reminder: What does it mean when a T Cell becomes anergic?

The T Cell becomes unresponsive to antigen stimulation but doesn't necessarily die

Central tolerance occurs where?

Primary lymphoid organs such as the thymus or bone marrow

Peripheral tolerance occurs where?

Outside the bone marrow and thymus

Describe the induction of tolerance in mature immunogen reactive cells (cells that are activated and are inducing an immune response)

Specific repressor cells are used to induce tolerance. This includes Treg cells, M2 macrophages, and NKreg cells

Describe how Treg cells induce tolerance in mature immunogen reactive cells

They will react with the same immunogen as another T cell. If it determines the immunogen to be self, it will secrete TGF-beta and IL-10 to stop other immune responses.

By inhibiting TH1, Treg cells can prevent ________ and by inhibiting TH2, Treg can prevent _________

autoimmunity; allergies

1 multiple choice option

The cytokines that Treg secretes (TGF-beta and IL-10) are responsible for stimulating what immunoglobulin to induce a mucosal immune response?

IgA

List three mechanisms to clinically induce tolerance in mature cells

Oral tolerance to proteins, high dose tolerance to aqueous proteins, and low dose tolerance to repeated, low doses

Describe the induction of tolerance that occurs in the gut (oral tolerance to proteins)

M cells will uptake antigens from the gut, which are then taken up by (CD103+) dendritic cells. The dendritic cells travel to lymph nodes and make IL-10. This induces Treg cell development and tolerance to that antigen

Give the different mechanisms of inducing self-tolerance

Negative selection in B and T cells, induction of anergy of auto-reactive B and T cells, and Treg cell suppression of autoimmune responses.

What is autoimmunity?

The immune response to self-antigens due to a loss of tolerance

Is autoimmunity always associated with an autoimmune disease?

No, some levels occur in everyone whether or not they have a disease

What are anti-idiotypic antibodies?

Antibodies that bind to the hypervariable regions (idiotypes) of other antibodies

What is the major function of anti-idiotypic antibodies?

To neutralizes autoantibodies and destroy abnormal cells

What can autoimmunity cause?

Inflammation and tissue damage

Give the possible mechanisms of autoimmune disease

Loss of tolerance

Failure to delete an auto-reactive T/B cell

Breakdown of peripheral tolerance

Antigen-nonspecific lymphocyte activation

Molecular mimicry

Abnormalities in lymphocyte interactions

Give some examples of breakdown of peripheral tolerance

Checkpoint failure and Treg deficiency

Give an example of antigen-nonspecific lymphocyte activation

Superantigens

What is molecular mimicry?

When an infectious immunogen resembles a protein in human tissue. Induces an autoimmune response

Give an example of abnormalities in lymphocyte interactions

Imbalances in the different subtypes of T helper cells, especially Treg cells

Give the general characteristics of autoimmune disease

Idiopathic (except when drug induced)

Multi-factor contribution

Most HLA-associated diseases are autoimmune

Multiple immune mechanisms

Inability to avoid immunogen and unknown cause results in suboptimal therapy or poor prognosis

What does idiopathic mean?

Unknown cause

Name some of the factors involved in multi-factor contribution

Sex, genetics, epigenetic, age, infection, and environmental

Give the classification of multiple immune mechanisms

Coombs and Gell classifications 1-4

Why is treatment of autoimmunity so difficult?

Normally, we would try to remove exposure to an immunogen to stop the immune reaction. With autoimmunity, the immunogen is apart of you and necessary for survival. It cannot be removed

Autoimmunity can involve any aspect of the (innate/adaptive) immune response

Adaptive

1 multiple choice option

What are two aspects of the adaptive immune response?

Cell mediated and humoral immunity

Describe the mechanisms an antibody can use to induce autoimmunity

They can act against cell surfaces or matrix antigens (type II) and induce complement or ADCC

They can act as antagonists and reduce the normal processes in our bodies

Could induce immune-complex diseases by binding up large antigens in the body (type III)

Give some examples of autoimmune diseases caused by antibodies

Hemolytic anemia, thrombocytopenia purpura, pemphigus, rheumatic fever, graves disease, myasthenia gravis, and type 2 diabetes

Give some examples of autoimmune diseases caused by T cells (type IV)

Type 1 diabetes, Rheumatoid arthritis, and multiple sclerosis

What T cell is primarily responsible for autoimmune disease?

TH17

Why is TH1 not found to be primarily responsible for autoimmune disease?

TH1 secretes IFN-gamma. If you get rid of IFN-gamma, you are more susceptible to autoimmune disease. It can still cause autoimmunity, just not primarily responsible.