BMS 545 Immunology Lecture Notes PDF

WELCOME- BMS 545 IMMUNOLOGY DECEMBER 2, 2024  THE REST OF THE SEMESTER (ALL MODULE 4)  12/2- Autoimmune Disorders  12/4- “What’s Wrong with Me?” Case Study  12/6- Final Immunology debrief:The Well Patient  12/9 Study Day- Pop in & out of my office from 3-5 pm in-person  12/10- Office ho...

WELCOME- BMS 545 IMMUNOLOGY DECEMBER 2, 2024  THE REST OF THE SEMESTER (ALL MODULE 4)  12/2- Autoimmune Disorders  12/4- “What’s Wrong with Me?” Case Study  12/6- Final Immunology debrief:The Well Patient  12/9 Study Day- Pop in & out of my office from 3-5 pm in-person  12/10- Office hours (virtual)  12/11- Immunology Exam at 1 pm ANNOUNCEMENTS  Office hours  Tu 4-5 pm virtual  Th 4-5 pm in-person  NO MORE DITKI ☺  Finishing up the review papers, grades will be posted by the end of the week! Why should you care?  OBJECTIVES  What is an autoimmune disorder?  What are the 3 ways autoimmunity occurs?  What are neoantigens and what are their consequences?  What are the types of hypersensitivity that autoimmunity mimics?  How does the body prevent autoimmunity?  Why does the body need small amounts of autoimmunity?  What is the impact of genetics, environmental triggers, and gender on autoimmunity?  Which genes are frequently associated with autoimmune diseases?  What are the hallmarks (signs, symptoms, treatments, etc.) of the specific conditions mentioned?  How do we treat autoimmunity (in general)?  DO NOT MEMORIZE NUMBERS OR RATES OF OCCURENCE  FRANKENSTEIN’S MONSTER  Hoarse and coarse voice  Fatigueable ptosis  Shuffling, difficult gait  Severely waxing and waning energy and physical capability  How was the monster created?  How might this cause his sx (“symptoms”)?  What is his condition? Big Picture  Normally, B and T cells are selected for survival if they can recognize but not react to self  *Remember B cells don’t need to recognize self since T cells typically activate them, and T cells know what “self” is  **B cells that recognize multivalent self antigen undergo receptor editing, and B cells that recognize monovalent self antigen are made anergic  Generally, immune cells are ignorant of proteins and antigens in normally immune privileged sites, e.g.:  Intracellular antigens  Testes & Uterus  Eye  Brain  The immune system is normally maintained in a relatively quiescent state, needing activation to for them to take effect  T-regs, M2 macrophages, & IL-10 are usually predominant  SELF TOLERANCE  Tolerance- failure of the immune system to respond to an epitope in an aggressive way  Most self-tolerance results from deliberate inactivation or destruction of lymphocytes bearing BCRs or TCRs that recognize & bind self-epitopes  Inactivation or destruction may occur during early development (central tolerance) or may be imposed on lymphocytes in the periphery (peripheral tolerance)  Central tolerance- occurs during early development of B cells in bone marrow & T cells in thymus  Normally, B & T cells that bind self-epitopes meet an apoptotic death- eliminating large numbers of potentially self- reactive cells  Major caveat = not ALL self-epitopes are to be found in primary lymphoid organs, e.g., those that arise during puberty  Peripheral tolerance- control or eliminate autoreactive B & T cells after they exit bone marrow or thymus  Anergy- a state of non-responsiveness in lymphocytes  Suppression- regulatory cells inhibit activity of other cells  ANERGY IN T- & B- CELLS  In T-cells  Binding of TCRs to appropriate pMHC I or pMHC II provides 1st signal for activation of T cells, but T cells must also receive 2nd signals from APCs (cytokines, etc.) for activation to proceed  Receipt of 1st signal but no 2nd signal = naive T cells enter state of inactivity (anergy)  Anergy can be broken & self-reactive CD8+ T cells can become activated → autoimmune disease?  Unclear whether CD4+ T cells can/can’t be anergized by comparable mechanisms because almost all activation of CD4+ T cells occurs with APCs (& APCs are the best)  In B cells  Naive B cells can be anergized if their surface immunoglobulins bind to monovalent self-antigens  SUPPRESSION  Tolerance to self-epitopes can also be induced by regulatory cells  Regulatory T-cells (Tregs) inhibit the activation of autoreactive cells  Autoimmune responses may be determined by relative balance in Th1/Th2 responses  e.g.Th2 response to a particular self-epitope may produce little or no pathology, but a Th1 response may produce an injurious cell-mediated inflammatory response such as DTH  e.g. intestinal epithelial cells produce anti-inflammatory Th2 cytokines (IL- 4, IL-10, & TGF-β) & create microenvironment promote production of IgA & inhibit inflammatory cell responses LOSS OF SUPPRESSION  Suppressor cells (e.g. Tregs & CD8 Suppressor cells) maintain peripheral tolerance  Evidence suggests that #s of suppressor cells decline with age, increasing risk that previously suppressed autoreactive lymphocytes can become active  A pattern of increasing risk with increasing age is seen in some autoimmune diseases, i.e. SLE  Difficult to differentiate between an increase risk because of changes from aging OR increased age also linked to more disease risk  Autoimmunity = loss of self tolerance Autoimmune disease tissue injury & What is inflammation result from an autoreactive immune response that gives rise to clinically Autoimmunity? manifested anomalies & demonstrable immunohistopathological changes All autoimmune conditions resemble type 2,3,4 hypersensitivity  AUTOIMMUNE DISEASES  Involve numerous different molecules, cells, & tissues  Can result from damage inflicted on cells & tissues by humoral responses, cell-mediated immune responses, or both  Systemic or diffuse due to distribution of target antigens  Ex. SLE & rheumatoid arthritis affect various joints & other body tissues  Some autoimmune diseases (i.e. SLE, Sjögren syndrome, & rheumatoid arthritis) occur more frequently in females than males  How does Autoimmunity Occur?  Autoimmune induction requires exogenous stimuli and endogenous abnormality  Internal error meets external irritant  Physical trauma exposes body’s immune system to normally sequestered potential antigens  Molecular mimicry= where antigenic trigger mimics self- proteins causing Abs to form that cross react with self AND pathogenic antigens  Constant exogenous stimuli in presence of endogenous abnormality leads to sustained pro-inflammatory signaling & lack of anti-inflammatory signaling  Immune system can become “stuck” in this mode & the predominant T & B cell lineages can become self-reactive leading to out-of-control autoimmunity  Genetics of Autoimmunity  No one gene is essential for autoimmune diseases  Single strongest genetic association with autoimmune diseases are HLA haplotypes  Higher consistency in monozygotic twins vs dizygotic twins  What does this mean?  Genetically normal self-HLAs can be modified to initiate auto-reactivity  Both by exogenous modification or by endogenous mutations Environmental Triggers of Autoimmunity Trauma Causes inflammation and releases normally sequestered potentially antigenic proteins Molecular mimicry Antigenic protein/peptide closely resembles self-proteins leading to auto-reactivity AND cross-reactivity Superantigen stimulation Endogenous or exogenous antigenic combination with MHC-II leading to activation of T cells via TCR This causes clonal expansion of auto-reactive T cells  TRAUMA: SEQUESTERED ANTIGENS  Some self-molecules are “sequestered” & normally not exposed to immune system  If they do become exposed → immune system may view them as foreign & attack  Ex. developing sperm within lumen of testicular tubules  Tubules are sealed off early in embryonic development (before immune system). Immune cells do not penetrate barrier & are never exposed to these self-molecules. If they are exposed by injury/surgery/vasectomy immune responses may (wrongly) attack  Possible cause of male sterility??  Immunologically privileged sites- sites in body associated with some degree of isolation from immune system  Include testicular tubules, cornea & anterior chamber of eye, brain, & uterine environment during pregnancy  May help to protect delicate structures damage & permanent injury that could follow strong inflammatory response  SEQUESTERED ANTIGENS  e.g. blood–brain barrier & blood-CSF barrier consists of dense, tightly packed vascular endothelium that limits flow of cells & large molecules from vasculature into brain, thus preventing immune system from infiltrating  Thought to be beneficial because strong inflammatory responses could easily inflict irreparable damage to the brain  CRYPTIC EPITOPES (COOL BAND NAME?)  Molecules may also possess a type of “immunologically privileged site”  3D configurations of some molecules may shelter epitopes in the interior of the molecule from contact with immune system  If molecule is altered by denaturation or cleavage,“hidden” internal epitopes may become exposed & available for recognition & binding by antibodies  These are cryptic epitopes  Ex. rheumatoid factor (RF), associated with inflammatory rheumatoid diseases  MOLECULAR MIMICRY  Infection by particular microbes is associated with subsequent development of specific autoimmune diseases  Especially after elevated pro-inflammatory cytokines  Inflammation from activated phagocytes → elevated levels of proinflammatory cytokines  Elevated cytokines MAY be sufficient to activate T cells without direct APC interaction  *Hypothesis- not definitively demonstrated in vivo, but tendency of autoimmune disease development after infection is suggestive  Antigenic molecules on some pathogens are similar enough to some host self-molecules that B- & T-cell responses against the microbial antigens → damage to host cells with similar molecules  Ex. cardiac damage from rheumatic fever after infection by Streptococcus pyogenes “strep” ASSOCIATION OF CARDIAC DAMAGE & RHEUMATIC FEVER  Rheumatic fever after infection (usually throat) by Group A strep  High levels of antibodies against bacterial M protein  IgG against M protein can cross-react with molecules on cardiac tissues  → antibody-induced injury can produce serious cardiac disease  Other tissues may also be affected, i.e. joints & kidneys ! Important to test patients with sore throats for strep & to begin antibiotic therapy ASAP before vigorous antibody responses against strep antigens can develop !  DIFFERENTIAL DIAGNOSIS  Neoantigens- “new” “antigens” not self-antigens but may lead to conditions that mimic autoimmunity  If the condition creating the neoantigens is removed, the condition should be resolved, but responses to true self-antigens should be permanent  “Molecular mimicry may explain tendencies towards autoimmunity during severe infection, e.g. by SARS- CoV2, but tends to fade as soon as the exogenous antigen is cleared” (Mustelin & Andrade, 2024)  Neoantigen hypothesis predicts that immunosuppressive drugs will reduce disease activity in TRUE autoimmune conditions  Neoantigens are also discussed with cancer, too, as they can be tumor-specific proteins that are not present in normal tissues. They are created by genetic mutations, viral infections, etc.  With cancer, they can be “helpful” because they are recognized as non-self by the body, which activates T cells to attack and destroy the cancer cells Biological Sex & Autoimmunity  Autoimmune diseases are more prevalent in women than in men  Of 19 common autoimmune diseases, 14 are more in women  Females have stronger adaptive responses  Estrogen & prolactin enhance adaptive immune responses  Conversely, testosterone decreases inflammatory cytokines, Th1 & NK cell lines, & increase Th2 (anti- inflammatory) cell lines XY XX  HUMORAL-ASSOCIATED AUTOIMMUNE DISEASE  Some autoimmune diseases result from binding of self-reactive antibodies, leading to type II & type III hypersensitivities  Antibodies responsible are usually IgG isotype (sometimes IgM)  Activation of complement & opsonization of injured cells promote inflammatory responses that increase damage on targeted cells & tissues  Autoreactive T cells are typically present, but their role is primarily activation of autoreactive B cells rather than directly attacking host  Examples:  Myasthenia Gravis: type II hypersensitivity  Hashimoto thyroiditis: type II hypersensitivity  Systemic lupus erythematosus (SLE): Type II? & Type III  Rheumatoid arthritis (RA): type III hypersensitivity  NMJ: MYASTHENIA GRAVIS (MG)  Neuromuscular junction (NMJ) disorder characterized by weakness & fatigability of skeletal muscles  Etiology:  Decrease in # of available acetylcholine receptors (AChRs) at NMJs due to type II hypersensitvity  Associated with thymoma, thymic hyperplasia, HLA-B8, & certain medications  Pathophysiology:  Autoantibodies directed against a protein of NMJ  Symptoms  Fluctuating muscle weakness & true muscle fatigue, e.g. fatigable chewing  Ptosis & Diplopia  Dysphagia & Dysarthria  Physical Exam  Ice-pack test- place ice on the patient's ptosis → ptosis improves  Labs: Serologic testing for autoantibodies  HASHIMOTO’S THYROIDITIS  Antibodies that attack thyroid tissue & eventually destroy thyroid gland, leading to hypothyroidism (underproduction of thyroid hormone)  Thyroid levels not always an accurate diagnostic tool for Hashimoto’s; can examine antibodies to thyroid peroxidase (TPO) & other anti-thyroid antibodies  Tx depends on if thyroid hormone levels are low enough to warrant thyroid hormone replacement  4-10x more common in women than men  In Caucasians, HLA-DR3, HLA-DR4  SLE: Sometimes it Really is Lupus  Antinuclear antibody positive, relapsing & remitting multisystem autoimmune disease  Both type II and III hypersensitivity (mainly III)  Type II → AB mediated host cell destruction (cytotoxic)  Type III → antigen-AB complex trapping in capillaries (primary mechanism)  Takeaways:  Butterfly (malar) rash on a young female with flu-like sx. May have rashes on areas exposed to sunlight  Raynaud phenomenon  HLA—DR3 RA:  HLA-DR4  Symmetrically polyarticular with proximal migration. Joint erosion is necessary for diagnosis  Loss of self-tolerance to citrullinated protein  Labs: Anti-citrullinated protein antibody (ACPA), rheumatoid factor (RF), C-reactive protein (CRP) positive (if RF negative → seronegative RA)  Has many extra-articular manifestations  Biggest “takeaways”  Female>Male  >1hr morning stiffness  ACPA positive  CELL-MEDIATED AUTOIMMUNE DISEASE  Type IV hypersensitivity responses involve cell-mediated injury leading to autoimmune disease  May include cytotoxic T-cell responses or macrophages driven by DTH responses  Inflammation generated can eventually involve numerous simultaneously ongoing responses  Particular antibodies may also be present, but they have not been demonstrated to contribute to disease pathologies  Examples involving type IV hypersensitivity responses:  Insulin-dependent diabetes mellitus (Type 1 diabetes): Type IV  Multiple sclerosis (MS): Type IV  T1DM  HLA—DR3 and DR4  T cell mediated (Type IV) destruction of B- islet cells in pancreas  Polydipsia, polyuria, polyphagia, weight loss, diabetic ketoacidosis  Elevated HbA1c (blood sugar) & plasma glucose often lead to small and large vessel disease  Causes innumerable consequences down the road  Autonomic damage  PNS damage  Kidney damage  Cardiovascular damage MS:  HLA—DRB1  Myelin and oligodendrocyte damage, spares PNS, CNS demyelinating disease  Myelin binding protein (MBP) autoantibodies  Leading cause of neurologic disability in young adults, esp. young females  Episodic or progressive multifocal CNS signs & symptoms  Epstein Barr Virus considered to be a causative agent  Damaged myelin → inflammatory infiltrates of lymphocytes and macrophages, antibody & complement deposition, activated microglia, & oligodendroglial cell loss  Autoimmune Progression  Once damage occurs, that inflammation can cause the sustained progression & amplification of the autoimmune pathology  Loss of self-tolerance to one antigen increases the likelihood of losing tolerance to another  Aberrantly increased B and T cell function without negative control → progression  Name of the game is control  Loss of tolerance control → autoimmunity  Lack of control of autoimmunity → inflammation → autoimmune progression  EPITOPE SPREADING  Epitope spreading- epitope that initiates a response leading to autoimmunity might not be epitope that is targeted by immune responses that develop later during the pathogenesis of disease  i.e. initial responses against infectious agent may result in damage that exposes self-epitopes in ways that subsequently trigger true autoimmune responses  e.g. In animal models of human MS, responses to viral epitopes regularly precede development of responses to specific epitopes associated with myelin sheath  Self-epitope targeted by an autoimmune response does not always remain constant over course of the disease  Some evidence that relapsing-remitting course autoimmune disease may be due to a series of independent responses generated against different self-epitopes rather than from responses to a single epitope → Difficult to devise therapies  Suspected to play role in SLE, IBD (Crohn’s disease & ulcerative colitis), MS & type 1 diabetes   Super simple: down regulate inflammation and downregulate the immune system  Glucocorticoids Treatment of  Monoclonal antibodies  NSAIDs Autoimmunity  Others  Lifestyle management is usually not enough, pharmaceutical therapy and lifestyle management together offers the best control  Current research is constantly changing  We don’t dx based on rates/prevalences  That being said, knowing the TRENDS and how they are Numbers and impacted by gender, age, ethnicity, etc. is important to be able to view the patient in full context and rates and why awareness they don’t  Women are more prone to autoimmune diseases than men really matter  Autoimmune disease incidence increases with age  Certain ethnicities are more likely to inherit specific HLA haplotypes  CHAPTER 16 SUMMARY  Tolerance is the failure to respond in an aggressive way against an epitope recognized by the immune system.  Autoimmunity results from a loss of self-tolerance through the failure to inactivate or eliminate self-reactive cells.  Central tolerance occurs in the primary lymphoid organs (bone marrow and thymus) during the early development of B and T cells.  Peripheral tolerance results from mechanisms that inactivate or eliminate B and T cells that are in circulation.  Anergy (inactivation) of B and T cells occurs when naive lymphocytes bind via their BCR or TCR ( “first signal”) but fail to receive the second signals provided by T cells (for B cells) and APCs (for T cells) that are necessary for activation.  Suppressor T cells inhibit responses by other immune cells.  Loss of self-tolerance may occur through molecular mimicry, epitope spreading, loss of suppression, or the exposure of sequeste red antigens.  Molecular mimicry involves the generation of responses to microbial epitopes that may cross-react with host epitopes that are structurally very similar to the microbial ones.  Epitope spreading occurs when a response to an epitope leads to the generation of responses to one or more other epitopes.  Suppressor T-cell numbers may decline with age, permitting other self-reactive cells to escape regulation and initiate autoimmune diseases.  Sequestered antigens are located in anatomical sites that are normally sheltered from the immune system by specialized anatom ic structures or other mechanisms.  Neoantigens are not self-antigens but may lead to conditions that mimic autoimmunity. If the condition creating the neoantigens is removed, the condition should be resolved. Responses to true self-antigens, on the other hand, should be permanent as a rule.  Numerous autoimmune diseases have been identified. Their effects are determined largely by the localization of the self-epitope. Some diseases, such as systemic lupus erythematosus and rheumatoid arthritis, are systemic and affect several body sites simultaneously. Others, such as Hashimoto thyroiditis and Sjög ren syndrome, affect specific tissues or organs.  Autoimmune pathology may result from antibody-initiated damage (hypersensitivity types II and III), cell-mediated responses (type IV hypersensitivity), or both.  Some autoimmune diseases have elevated frequencies in individuals carrying certain HLA genes. The statistical association bet ween the disease and the HLA gene is expressed as the relative risk.