Autoimmune Disease

Cells of the Immune System

Source: http://www.biologymad.com/

Reviewing the Cells of the Immune System Eosinophil

Erythrocyte

Monocyte

Lymphocyte

Neutrophil polymorph

Basophil

Lymphocytes of the Immune System

B Lymphocytes:

Immunocompetency occurs in bone marrow Produce Antibodies Conduct Humoral Immunity

T Lymphocytes:

Immunocompetency occurs in thymus Non antibody producing cells Conduct Cellular Immunity

www.academic.brooklyn.cuny.edu/biology/bio4fv/page/aviruses/cellular-immune.html

Lymphocyte Maturation

Antibody Mediated Immunity

Cell Mediated Immunity

B Cells Mature in Marrow

Stem Cells of the Bone Marrow Released into blood, spleen, lymph

T Cells Mature in Thymus

Identify Antigens

Macrophages carry foreign cells to T Helper cells T Helper cells (Th) produce proteins

B Cells Replicate to form Plasma cells

B Memory Cells

Release Antibodies

Secrete Interleukins Replicate Cytotoxic (killer) T (Tc) Cells Effector Tc Cells Tm Memory Cells

Secrete lymphokines Stimulates Phagocytosis

Forms of Immunity

Antibody Mediated Immunity

Cell Mediated Immunity

Helper T cells recognize non self antigens and stimulate B cells to produce antibodies B cells release antibodies which bind to non self antigens present on infected cells B cells complete their maturation upon binding to non self antigens and destroying infected cells

Macrophages phagocytize pathogens Upon phagocytosis macrophages present non self antigens on their membranes Helper T cells recognize non self antigens and recruit cytotoxic T cells Cytotoxic T cells destroy infected cells

Antibody Mediated Immunity

Animation of Antibody Mediated Immunity

What kind of cell does the macrophage activate in the humoral immune response? What occurs during the effector phase of the humoral response?

http://press2.nci.nih.gov/sciencebehind/immune/immune00.htm

Cell Mediated Immunity:

http://press2.nci.nih.gov/sciencebehind/immune/immune00.htm

What happens when the bodys lymphocytes fail to recognize its own cells and tissues as such?

Autoimmune Disease

Self tolerance is lost Specific adaptive immune responses mounted against self antigens Inability to eliminate antigen leads to chronic inflammatory process Ehrlich termed this horror autotoxicus

Autoimmune Diseases

Failure of autoantibodies and T cells to recognize own cells Autoantibodies and T cells launch attack against own cells Perhaps due to overactive or an overabundance of helper T lymphocytes

Autoimmune disease susceptibility

Genetic predisposition

Twin studies (Diabetes: 20% monozygotic vs. 5% dizigotic) Family studies HLA genotyping

Association with MHC genotype

Possible Causes:

Potential Treatments:

Inefficient lymphocyte programming Self proteins circulate without having been exposed to system
(ex: sperm, eye lens, thyroid)

Control inflammation

(ex: diabetes mellitus)

Immunosuppressive Medication

(ex: corticosteriods, cyclosporin, methotrexate)

Reactions between selfantigens and antibody production against foreign antigens

Therapeutic Antibodies against specific T cell molecules

(with fewer side effects)

Diagnosis: Autoimmune Disease

Genetic predisposition

coding for the variety of MHC molecules

Demographics

most common among middle aged women

Additional viral infections Disease specific environmental factors Aging, stress, hormones, pregnancy

Examples of Autoimmune Diseases

Multiple sclerosis Myasthenia gravis Crohns disease Graves disease Type 1 Diabetes mellitus Rheumatoid arthritis Psoriasis Scleroderma Systemic lupus erythematosus

Autoimmunity involves T cells

Ability of a T cell to respond is determined by MHC genotype It has been hypothesized that susceptibility to an autoimmune disease is determined by differences in the ability of allelic variants of MHC molecules to present autoantigenic peptides Alternatively, self peptides may drive the positive selection of developing thymocytes that are specific for particular autoantigens.

Peripheral B-cell anergy

Several ways in which infectious agents could break self tolerance

Association of infection with autoimmune disease

Some body sites are immunologically priviledged

Damage to an immunologically privileged site can induce an autoimmune response

AUTOIMMUNE DISEASE KEY CONCEPTS

Recognition of autoantigens by lymphocytes is critical

Tissue destruction not just autoimmune cells must be present AD involve self-reactive T cells

AD induction almost always depends on triggering of autoreactive CD4+ T cells

MECHANISMS OF BREAKING OF SELF-TOLERANCE

Disruption of self or tissue barrier

Infection of antigen presenting cell Binding of pathogen to self antigen Molecular mimicry superantigen

EXAMPLES 0F ORGAN-SPECIFIC AND NON ORGAN-SPECIFIC (SYSTEMIC) AUTOIMMUNE DISEASES

Organ-specific Hashimoto thyroiditis Thyrotoxicosis Addisons disease Atrophic gastritis Juvenile diabetes mellitus Multiple sclerosis Non organ-specific Systemic lupus (SLE) Rheumatoid arthritis (RA) Scleroderma Dermatomyositis Mixed connective tissue disease (MCTD) Sjgrens syndrome

ORGAN-SPECIFIC AND NON ORGANSPECIFIC AUTOIMMUNE DISEASES

Organ-specific

Autoimmune attack vs. self-antigens of given organ It results in a damage of organ structure and function Treatment is focused on the replacement of organ function

Non organ- specific (systemic) Widespread self-antigens are targets for autoimmune attack Damage affects such structures as blood vessels, cell nuclei etc. Treatment is aimed to inhibit excessive activation of the immune system

AUTOREACTIVE T CELLS ARE PRESENT IN LYMPHOID TISSUES AND BLOOD

Central tolerance does not delete T cells autoreactive to organ-sequestered antigens and cryptic epitopes Subset of these T cells are potentially pathogenic These T cells must be kept tolerant by:
a. b. c. d.

elimination maintenance of immunologic ignorance functional inactivation (anergy) suppression

AD ARE COMPLEX GENETIC TRAITS

Multiple genes determine susceptibility to AD

No particular gene is necessary or sufficient for disease expression (relatively low gene penetrance)
MHC and multiple non-MHC genes are involved Epistasis (interaction of susceptibility genes) Genetic alleles increasing susceptibility are relatively frequent in the general population

EXAMPLES OF GENE DEFECTS IN AUTOIMMUNITY

Multiple sclerosis particular alleles of HLA-DR (DRB1*1501, DRB5*0101)

Systemic lupus lack of C1q and C4 Genetically determined low expression of given self-antigen in the thymus

Mutation (usually deletion) of autoimmune regulator-1 gene (AIRE-1)

IMPACT OF ENVIRONMENTAL TRIGGERS ON INDUCTION OF AD

Virus clustering (RA, Sjgrens s., SLE, MS) Infectious microorganisms (molecular mimicry see later) Geographic clustering Sun exposure (SLE) Exogenous estrogens, sex hormones in general

MOLECULAR MIMICRY
Definition: Determinants of infectious agent mimic a host antigen and trigger self-reactive T-cell clones to attack host tissues. Examples:
Stromal keratitis due to herpes simplex virus type I Rheumatic fever due to group A streptococcus SLE due Epstein-Barr virus cross reactive with nuclear Sm antigen Lyme artrhritis due Borrelia burgdorferi reactive with LFA-1 (lymphocyte function antigen-1)

EPITOPE SPREADING

Definition: Initial response to one self determinant (one peptide) could expand to involve additional determinants on the same molecule as well as additional self-proteins. It explains how a response to one cryptic epitope can mature into a full-blown autoimmune response Examples:

anti-Sm to U1RNP anti Ro/SS-A to anti-La/SS-B lead to lupus-like disease

HLA CLASS II EXPRESSION ON TISSUE CELLS IN AUTOIMMUNE DISEASES

Hashimoto thyroiditis follicular cells of the thyroid Type I diabetetes beta cells of Langerhans islets Primary biliary cirrhosis cells of billiary ducts Autoimmune hepatitis hepatocytes

HLA CLASS II EXPRESSION ON TISSUE CELLS IN AUTOIMMUNE DISEASES - 2

Rheumatoid arthritis synovial cells Sjogren syndrome epithelium of salivary ducts Multiple sclerosis glial cells Chronic iridoscleritis pigment epithelium of retina Crohns disease epithelium of small intestine

OTHER FACTORS FAVORING AUTOIMMUNITY

1.

Overproduction and/or dysregulation of cytokines

Disturbances of apoptosis Adjuvant effect of microorganisms Pre-existing defects in the target organ Direct stimulation of autoreactive cells by foreign antigen

2. 3. 4.

5.

PATHOGENICITY OF HUMAN AUTOANTIBODIES

Autoimmune blood dyscrasias Antiphospholipid syndrome Myasthenia gravis Thyrotoxicosis (Graves disease) Male infertility Anti-receptor mediated diabetes mellitus Goodpastures syndrome Immune complexes (SLE, RA)

DIAGNOSTIC STEPS IN SYSTEMIC LUPUS

Immunoglobulin level ( >90%) Complement components level (60%) Anti-nuclear antibodies(ANA)(1:80< 95%) Anti-ds DNA Ab (90-95%) Rheumatoid factor (30%) Immune complex deposits in the skin(60%) in kidney (90%)

THERAPY OF AUTOIMMUNE DISEASES:

I. SELF-ANTIGEN SPECIFIC
1. 2. 3.

4. 5.

Antibodies vs. autoreactive TCR Vaccine containing autoreactive TCR Administration of peptides TCR antagonists Parenteral infusion of autoantigen or cDNA Oral administration of autoantigen

Comment: all above are at the stage of experiment

THERAPY OF AUTOIMMUNE DISEASES:

II. ANTIGEN NON-SPECIFIC
1. 2.

3.
4. 5. 6.

Monoclonal antibodies vs.T cells -CD2, CD3, CD4 Antibodies vs. CD28, CD40L (modulation of T cell APC interaction) Antibodies vs. cell adhesion molecules (VLA-4, ICAM-1) and chemokines Intravenous infusion of immunoglobulin (IVIG) Neutralization of proinflammatory cytokines Administration of anti-inflammatory cytokines