Lecture 23. Autoimmune Disorders - PDF

Explain how autoimmune Learning 1. disorders occur and how they are related to tolerance. Objectives Describe selected autoimmune 2. disorders. Indicate the main clinical 3. features of select autoimmune...

Explain how autoimmune Learning 1. disorders occur and how they are related to tolerance. Objectives Describe selected autoimmune 2. disorders. Indicate the main clinical 3. features of select autoimmune disorders Explain the immune 4. mechanisms that lead to those clinical features. Describe treatment and 5. therapeutic options for selected autoimmune disorders. 1 Autoimmune diseases 2  Autoimmune disease Autoimmune diseases are generally mediated by either antibodies or T cells, although other cells may add to the pathology (e.g. mΦs, neutrophils, eosinophils) o these antibodies may be agonistic (stimulate an improper response) or antagonistic (suppress a normal response) Autoimmune disease may be organ specific (diabetes → pancreas) or systemic (SLE) 3  Autoimmune disease and tolerance Can develop in two ways o failure to develop tolerance to self- antigens o dysregulation of some part of the immune system leads to loss of tolerance to self Responses tend to be chronic since the antigen is self & cannot always be removed o constant insult to tissues can be fatal if the target antigen is in a vital organ (e.g. kidney) 4  Autoimmune disease and tolerance This lack of tolerance can occur during lymphocyte development (central tolerance) or be induced by other mechanisms such as molecular mimicry (peripheral tolerance) o aberrant activation of tissue APCs which present self-antigens can activate T cells that are auto-reactive o molecular mimicry when the epitope of an infectious agent is the same (or very close) to self o non-specific T cell activation by a pathogen superantigen can activate auto-reactive T cells o trauma or injury can expose self-antigens 5  Autoimmune disease – contributing factors Every individual possesses mature, circulating autoreactive lymphocytes o autoimmune disease occurs in only about 3% of the population Several factors can contribute to the etiology or development of an autoimmune disease o genetics (HLA are some of the most common) o anatomic alterations – injury, citrullination o infectious agents Environmental o exposure to toxic chemicals exposures 6  Autoimmune disease – molecular mimicry Rheumatic Heart Disease https://pathology.jhu.edu/autoimmune/causes/ 7  Autoimmune disease – superantigen T cell activation Superantigen T cell activation T cells are activated that do not recognize the peptide being presented The superantigen from the pathogen holds the MHC II molecule to the TCR, making the T cell “believe“ it recognizes the peptide being presented This results in polyclonal activation of many T cells instead of just the correct/specific T cell 8 Abbas: Cellular and Molecular Immunology, 2018  Autoimmune disease Examples of Autoimmune Disorders: Sjögren’s syndrome Affect 3% of the US Scleroderma population – ~10 Celiac disease million individuals Bechet’s disease Diabetes mellitus, type 1 Clear gender bias, with women more affected Atrophic gastritis than men at a rate of Psoriasis 2:1 (may be due to periods of extensive Multiple Sclerosis stress – pregnancy, or Inflammatory Bowel Disease hormonal changes) Guillain-Barré Syndrome Autoimmune Lymphoproliferative Synd Pemphigus vulgaris Graves disease Hashimoto thyroiditis 9  Autoimmune disease Systemic autoimmune diseases o RA o Autoimmune Hemolytic Anemia (AIHA) o Guillain-Barré syndrome Organ-specific autoimmune diseases o Vitiligo o Chron’s disease o Ulcerative colitis 10  Arthritis classifications Osteoarthritis ACCPA+ ACCPA- S. Aureus Gout B. Burgdorferi TB Anti-cyclic N. gonorrhoeae citrullinated peptide antibodies There are over 100 different types of arthritis 11 Citrullination is a modification of self-ags which can lead to RA  Rheumatoid Arthritis There are 2 major subtypes of inflammatory RA o + anti-cyclic citrullinated peptide antibodies (ACCPAs) o - anti-cyclic citrullinated peptide antibodies ACCPA’s develop when a positively charged arginine is replaced by a polar, but neutral, citrulline o ACCPA’s are detected in ~67% of RA pts o + ACCPA’s indicate a higher probability that the disease will progress in severity 12  Rheumatoid Arthritis Etiology remains unclear Typically develops in individuals 60+ yoa Mediated, in part, by rheumatoid factor (RF) o immune complexes form when antibodies are made against the Fc part of IgG or IgM, creating small complexes that deposit in joints & drive the inflammatory response o certain diseases, besides RA, can be + for RF ▪ SLE, HepC, Sarcoidosis, MCTD o TH1 & TH17 cells also secrete cytokines that mediate some of the pathology 13  Rheumatoid Arthritis Genetic Environmental pre-disposition exposures Failure of Development tolerance mech of ACCP abs 14 Abbas: Cellular and Molecular Immunology, 2018  Rheumatoid Arthritis ~40% of RA patients experience symptoms in other parts of the body o skin o eyes o lungs o heart o kidneys o salivary glands o blood vessels o bone marrow 15  Rheumatoid Arthritis Treatment o DMARD’s ▪ methotrexate, hydroxychloroquine o small molecule inhibitor DMARD’s (_nib drugs) ▪ Tofacitinib or baricitinib → JAK inhibitors o biologics (_mAb drugs) ▪ Humira & Remicade mAb’s that bind to & block the TNF-α cytokine from binding to TNF-αR (receptors) on cells ▪ Enbrel is a soluble TNF-α receptor which blocks the TNF-α cytokine from binding TNF-αR ▪ Actemra binds IL-6R blocking IL-6 binding 16  Hemolytic Anemias A group of disorders characterized by the 1) premature destruction or removal of red blood cells 2) which exceeds the capacity of the bone marrow to replace them or increase production of RBCs. There are many causes of early destruction or removal of RBCs o Immunologic (immune, autoimmune) o Trauma (burns, damage from artificial valves) Extrinsic o Toxins (venomous snakes or spiders) o Infections o Drugs o Genetic disorders Intrinsic ▪ enzyme defect (pyruvate kinase, G6PD) ▪ intrinsic erythrocyte disorder (sickle cell, spherocytosis) 17 ▪ hemoglobin abnormalities (thalassemia)  Autoimmune Hemolytic Anemia (AIHA) Immune/autoimmune hemolytic anemias result from the development, or receipt, of antibodies directed against RBC membrane antigens o leads to accelerated removal or destruction of RBC’s Antibodies of immune hemolytic anemias can be: o made against normal RBC constituents (e.g. Rh) o made against antigens modified when bound to the RBC (e.g. haptenation of drugs to the RBC) The source of these antibodies can be: o autoantibodies (autoimmune hemolytic anemia) o alloantibodies introduced into the patient from a donor (alloimmune hemolytic anemia) 18  Autoimmune Hemolytic Anemia Immune hemolytic anemias are acquired disorders o approx. half of these cases are idiopathic o the remainder are secondary, associated with neoplasms, infections, vascular diseases (RA, SLE), or drug reactions o the most common classes of immunoglobulins are IgG or IgM ▪ IgG auto-antibodies are more likely to induce Fc receptor-mediated opsonization in either the spleen or liver, but can induce complement activation ▪ IgM auto-antibodies induce complement, most often resulting in MAC lysis (less common with IgG) 19  Autoimmune Hemolytic Anemia Drug-induced AIHA (diAIHA) o this type of AIHA may be intravascular or extravascular and can occur months after removal of the drug o haptenation of certain drugs to the RBC surface generates IgG antibodies which result in Fc receptor-mediated opsonization by splenic macrophages o the most common drugs that are involved in diAIHA are: ▪ cephalosporins (now most common), (IV) penicillin, isoniazid, α-methyldopa, quinine, & insulin 20  Autoimmune Hemolytic Anemia Alloantibody Immune Hemolytic Anemias o Rh & ABO blood antigens are the most common targets of alloantibodies o hemolytic disease of the newborn occurs when Lecture 15, maternal IgG crosses the placenta because the slide 6 mother has been sensitized during a previous pregnancy to antigens present on the fetal RBCs that the mother lacks ▪ Rh, Kell, Duffy, Kidd, or ABO o ABO incompatibility can occur when a blood transfusion introduces IgM alloantibodies from the donor which recognize antigens present on the RBCs of the recipient 21  Guillain-Barré Syndrome An acute, progressive, monophasic paralytic neuropathy resulting from aberrant autoimmunity, typically in response to a causative infection o antecedent infection is the most common cause ▪ Campylobacter jejuni (most common) CMV, EBV, & Mycoplasma pneumoniae are commonly identified antecedent pathogens During the progressive phase, autonomic dysfunction manifests in two-thirds of patients, causing ileus, arrhythmia, and/or contributing to respiratory failure 22  Guillain-Barré Syndrome Immunologic autoimmune mechanism o involves T cells, B cells/abs, mΦs & complement ▪ γδ T cells are more prominent in those whose disease was triggered by C. jejuni ▪ Cross reactive abs to C. jejuni epitope are made (molecular mimicry) & bind to nerve cells https://www.nature.com/articles/nrneurol.2014.121/figures/2 23  Guillain-Barré Syndrome Treatment o plasmapheresis (plasma exchange or PE) – removes autoantibodies o IVIg – can dilute antibodies with non-specific (pooled) antibodies so autoantibodies are blocked o anti-inflammatory corticosteroids 24  Organ-Specific Autoimmune disease Organ-specific autoimmune diseases o occur when lymphocytes or antibodies bind to the cell resulting in lysis and/or an inflammatory response in the organ o eventually the damage causes a decline in organ function or a change in the organ 25  Vitiligo A condition that causes melanocyte destruction & subsequent patchy depigmentation of the skin & hair follicles There are two main types of vitiligo o non-segmental ▪ symmetrical white patches on both sides of the body o segmental (far less common) ▪ affects just one area of the body 26  Vitiligo ~50% of cases appear before the pt is 20 yoa, but can develop at any age o disease with onset after the age of 40 has a significant association with autoimmune thyroid disease Causes o autoimmune attack of melanocytes o genetic mutations 27  Vitiligo Triggers that can lead to vitiligo o stressful events, such as childbirth o skin damage, such as severe sunburn or cuts (this is known as the Koebner response) o hormonal changes to the body, such as puberty o problems with the liver or kidneys o exposure to certain chemicals 28  Vitiligo Immunologic autoimmune mechanism o a trigger causes the melanocytes to express altered self-antigens & DAMPs while undergoing apoptosis o APC takes up & presents the melanocyte altered self-antigens, present them to CD8+ & CD4+ T cells which release pro-inflammatory cytokines Mala Singh, Ashwin Kotnis, Shahnawaz D. Jadeja, Anushree Mondal, Mohmmad S. Mansuri & Rasheedunnisa Begum (2019) Cytokines: the yin and yang of vitiligo pathogenesis, Expert Review of Clinical Immunology, 15:2, 177-188 29  Vitiligo Immunologic autoimmune mechanism o B cells also recognize melanocyte antigens & become activated, generating antibodies which attack the melanocyte cells o CTL’s are the main effector mechanism damaging the melanocytes, creating the loss of color Mala Singh, Ashwin Kotnis, Shahnawaz D. Jadeja, Anushree Mondal, Mohmmad S. Mansuri & Rasheedunnisa Begum (2019) Cytokines: the yin and yang of vitiligo pathogenesis, Expert Review of Clinical Immunology, 15:2, 177-188 30  Vitiligo Treatment o the choice of treatment depends on the pts age, how much skin is involved & where, how quickly the disease is progressing ▪ medications & light-based therapies are available to help restore skin color or even out skin tone o drugs that control inflammation ▪ corticosteroids o medications that affect the immune system ▪ ruxolitinib (Opzelura – JAK kinase inhibitor) ▪ calcineurin inhibitors (disrupt txn of IL-2, preventing T cell activation, prolif & diff) 31  Chron Disease One of 2 disorders that comprise IBD o inflammatory condition throughout the GI tract ▪ can be throughout the GI tract or in segmented areas ▪ most commonly in the lower part of the small intestine (ilium) & upper part of the large intestine ▪ which part(s) of the GI tract that develop inflammation is unique to each person o autoantibodies can attack cells in the intestinal region of the GI tract o flare ups can be associated with diet or medications 32  Chron Disease Begins with inflammation & abscesses in the crypts in gut mucosal tissues o these progress to focal aphthoid ulcers ▪ these ulcers can occur in the tissues over the Peyer’s patches or within the D-MALT tissues ▪ they create the “cobblestone” appearance of the bowel o transmural spread of inflammation leads to thickening of the bowel wall & mesentery 33  Chron Disease Both adaptive & innate responses are involved in the pathology of CD o inflammation is caused by the immune response against luminal bacterial antigens o immune cells infiltrate the gut ▪ CD4+, CD8+, B cells, NK cells, monocytes CD4+ T cell subtypes include TH1 & TH17 o the innate immune system is also uniquely involved in CD o variants of the muc2 gene reduce mucus production o nod2 mutations are linked to CD 34  Chron Disease There is an overproduction of inflammatory cytokines o IL-12, TNF-α, IL-23, & IL-34 ▪ IL-34 expression is more pronounced in areas of active inflammation o IL-21 converts B cells to granzyme-B expressing B cells (GZMB+ B cells) ▪ granzyme-B possesses cytotoxic activity against the intestinal mucosa, causing epithelial damage 35  Chron Disease Treatment Vedolizumab (Entyvio) Infliximab (Remicade) Adalimumab (Humira) Ustekinumab (Stelara) Risankizumab (Skyrizi) 36  Ulcerative Colitis One of 2 disorders that comprise IBD o chronic inflammatory disorder of the colonic mucosa o usually begins in the rectum ▪ extends proximally in a continuous manner through part of, or the entire, colon 37  Ulcerative Colitis Pathophysiology o reduced mucin production o damage to the epithelial barrier leads to increased permeability ▪ reduces the regulation of tight junctions o atypical TH2 response is mediated by non- classic NKT-cells producing IL-4 & IL-13 ▪ IL-13 exerts cytotoxic functions against epithelial cells, including induction of apoptosis & alteration of the tight junctions 38  Ulcerative Colitis Pathophysiology o NKT- cells produce cytokines IL-4 & IL-13 ▪ IL-13 provides a positive feedback effect on the NKT-cells, amplifying tissue injury o TNF-α is elevated in the blood, stool samples & mucosa of patients with UC ▪ TNF-α increases inflammation ▪ several of the biologic medications are targeted at this cytokine (anti-TNF-α) 39  Ulcerative Colitis Pathophysiology o pro-inflammatory cytokines upregulate the expression of adhesion molecules (e.g. MadCAM-1) on the vascular endothelium of mucosal blood vessels o adhesion molecules like MadCAM-1 capture leukocytes & promote extravasation into the tissue, thus perpetuating the cycle of inflammation 40  Ulcerative Colitis Treatment Vedolizumab (Entyvio) Infliximab (Remicade) Adalimumab (Humira) Ustekinumab (Stelara) Golimumab (Simponi) 41  Chron Disease vs. Ulcerative Colitis Chron Disease Ulcerative Colitis Any area of the GI tract (mouth to Colon and rectum anus) Transmural (across the wall or the Mucosa and submucosa GI tract) Rectal bleeding is rare Rectal bleeding is a characteristic symptom Continuous pain Intermittent pain coinciding with bowel movements https://www.gastroconsa.com/patient- education/crohns-disease/ 42