Γιάννης Ρούτσιας, MD, PhDœΑΘΗΜΑΤΑ... · Autoimmune Hemolytic Anemia ....
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Transcript of Γιάννης Ρούτσιας, MD, PhDœΑΘΗΜΑΤΑ... · Autoimmune Hemolytic Anemia ....
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