Αυτοανοσία

Γιάννης Ρούτσιας, MD, PhD Επικ καθηγητης Ανοσολογίας/Μικροβιολογίας,

ΕΚΠΑ

Autoimmunity

Autoimmunity Origins Horror autotoxicus:

Literally, the horror of self-toxicity.

A term coined by the

German immunologist Paul Ehrlich (1854-1915) to describe the body's innate aversion to immunological self-destruction.

History Continued

This concept of autoimmunity as the cause of human illness is relatively new, and it was not accepted into the mainstream of medical thinking until the 1950s and 1960s.

Pick an organ, any organ . . . Autoimmunity can affect ANY organ/organ system in the human body

Pemphigus

Multiple Sclerosis

Sjogren’s Syndrome

Rheumatic Fever

Autoimmune Hepatitis

Ulcerative Colitis

Goodpasture’s Syndrome

Diabetes

Autoimmune Uveitis

Autoimmune hemolytic Anem

Addison’s Disease

Rheumatoid Arthritis

Autoimmune Oophoritis

Figure 11-37

Requirement of T cell help in B cell responses

Autoimmune diseases result from defective self-tolerance

Genes and Autoimmunity

The concept that a single gene mutation leads to a single autoimmune disease is the EXCEPTION not the rule.

Because of this autoimmune diseases are generally classified as complex diseases as there is not a single “pinpoint-able” gene

Exceptions to the Rule – Simple Genetic Autoimmune Illnesses

Disease Gene Mechanism

APS-1 (Autoimmune polyglandular syndrome type 1)

AIRE Decreased expression of self-antigens in the thymus, resulting is a defect in negative selection

IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, X-linked)

FOXP3 Decreased generation of Tregs

ALPS (autoimmune lymphoproliferative syndrome )

FAS, FASL Failure of apoptotic death of self reactive T or B cells

Classification of autoimmune diseases by etiology

Exposure of antigens of an immune-privileged site

Recognition of neoepitopes Infection Molecular mimicry Infection inappropriate expression of

MHCII

Sympathetic ophthalmia: Physical trauma in one eye can initiate autoimmune response to both eyes

Figure 11-28 Ciliac Disease: wheat flour gluten peptide-specific CD4+ T cells. HLA-DQ2/8 presents the peptide to CD4 T cells.

CD4+ T cells activate macrophages and B cells. Development of anti-transglutaminase auto-antibodies. Destruction of villi structure

Food allergy Autoimmune disease

Infection plays an important role in causing autoimmunity. Molecular mimicry: antibodies to pathogens cross-react against host antigens. e.g. Rheumatic fever

Pathogens

Figure 11-32

Infection/inflammation induces IFN-, which induces MHC class II expression on tissue cells and facilitates autoimmunity.

IFN-γ is secreted by T helper cells (specifically, Th1 cells), cytotoxic T cells (TC cells) and NK cells

Immune Thrombocytopenic Purpura (Θ.Πορφύρα) Antibodies, part of the body's immunologic defense against infection, attach to blood platelet, cells that help stop bleeding, and cause their destruction. Thrombocytopenia refers to decrease in blood platelet. Purpura refers to the purplish-looking areas of the skin and mucous membranes (such as the lining of the mouth) where bleeding has occurred as a result of decreased platelet. Some cases of ITP are caused by drugs, and others are associated with infection, pregnancy, or immune disorders such as systemic lupus erythematosus. About half of all cases are classified as "idiopathic," meaning the cause is unknown.

type 2

Nature Immunology 2, 777 - 780 (2001)

Sex differences in autoimmunity

Classification of autoimmune diseases by tissues affected

• develops when a specific adaptive immune response is mounted against a self antigen(s)

• sustained because of inability to eliminate antigen - chronic inflammation

(Goodpasture’s Syndrome: anti-glomerular basement antibody disease)

Examples of Organ Specific

Lungs of a patient with Goodpasture’s

Vitiligo Hashimoto’s disease (thyroiditis)

Examples of Systemic Autoimmunity SLE

Examples of Systemic Autoimmunity Sjogren’s Syndrome

Three Types of Autoimmune Disease

Αντίδραση υπερευαισθησίας:

Type II

Type III

Type IV

Classification of autoimmune diseases by immunopathogenic mechanism

Classification of Hypersensitivity

Type II Autoimmune Diseases

Autoimmune Hemolytic Anemia

Antibodies To Vascular Basement Membranes Cause Goodpasture’s Disease That Affects Renal Glomeruli and Lung Alveoli

Type II Autoimmune Diseases Include Autoimmunity Against Cell Surface Receptors

Mechanism For Thyrotoxicosis (Graves’ Disease) Is Anti-TSH Antibody

Myasthenia Gravis

Type I diabetes

Circulating IgG Autoantibodies Can Cross Placenta To Affect Fetus

Autoantibodies can be passed from affected mothers to their new born babies: Graves’ disease

Types III/IV Autoimmune Diseases

Classification of Hypersensitivity

Type III – Immune-complex disease

Systemic Lupus Erythematosus

Systemic Lupus (wolf) Erythematosus (skin rash)

This facial rash is found in some SLE patients Affects 1 in 500 African or Asian women Abs to histone and DNA

Systemic Lupus Erythematosus (SLE)

autoimmune disease prevalence: 1/500 - 1/1000 predominantly affects women

SLE -kidney

Deposition of immune-complexes within loops of glomerulus leads to abnormal kidney function

SLE - skin The lupus rash is typically

brought on by sun exposure ‘photosensitivity’

Immune-complexes and inflammatory cells seen in the skin

characterized by production of a variety of autoantibodies directed against predominantly nuclear antigens

tissue damage usually caused by autoantibody deposition with responses similar to Type II and III hypersensitivity reactions

Autoantibodies in SLE

The pathology lies in the autoAb

However, to date, there have been over 116 identified autoAb in SLE Semin Arthritis Rheum. 2004 Oct;34(2):501-37.

Therefore the exact auto-antigen is hard to discern

TLRs

TLR7 and TLR9 have been implicated in SLE

Both are receptors for apoptotic products from cells

Stimulation of both leads to production of Type 1 IFNs which in turns leads to autoantibody production in SLE

FcRs and TLRs combine forces

These two pathways converge in the plasmacytoid DC to make even more IFN And increased levels of Type 1 IFNs (a/b) lead to WORSE prognosis in SLE

Type IV – Immune-complex disease

Multiple sclerosis (Experimental Autoimmune Encephalomyelitis )

Multiple Sclerosis (Έλυτρο μυελίνης)

(Νευράξονας)

Experimental Autoimmune Encephalomyelitis A Model For Multiple Sclerosis

Genetic associations

HLA associations with various autoimmune diseases

Relative risk - observed number of patients carrying a particular HLA allele compared to the expected number based on the prevalence of the HLA allele in the general population

In IDDM disease susceptibility is most closely associated with a DQ polymorphism at position 57

Original association with DR3 and DR4 alleles is due to tight genetic linkage between these alleles and DQ alleles that confer susceptibility

most abundant DQ has aspartic acid at position 57, in diabetic individuals valine, serine, or alanine is found at this position

Aspartic acid forms salt bridge

No salt bridge: end of MHC molecule is open leading to altered peptide binding

Treatment

The key to treating autoimmunity is

immunomodulation

Treatment Options • Anti-inflammatory drugs

• NSAIDS, Corticosteroids • Immunosuppressant drugs

• Methotrexate • Plamapheresis • Cell Blocking Reagents

• aCD20 (Rituxan) • aCD3 (Teplizumab)

• Cytokine Blocking Reagents • TNF (Humira, Enbrel)

The end