Patho Lecture 5 (Diseases of the Immune System)

Allergy & Hypersensitivity

Immune responses in which the antigen is an environmental agent, food, or drug that is NOT intrinsically harmful

What antibodies mediate Type I Hypersensitivity (Allergic) responses?

IgE antibodies

What does a Type I allergic response cause?

Causes release of histamine, leukotrienes, and prostaglandins from mast cells and basophils

Is Type I hypersensitivity immediate or delayed?

Immediate

What does "atopic" mean in Type I hypersensitivity?

Sustained, inappropriate IgE responses to common environmental antigens encountered at mucosal surfaces, usually familial association

What are 3 examples of Type I Hypersensitivity?

- Acute anaphylaxis

- Hay fever

- Food allergies

What are the 7 steps of Type I Hypersensitivity?

1) Exposure to allergen (e.g., inhale pollen)

2) In response to the allergen invader, T-helper 2 cells tell B-cells to make antibodies (IgE)

3) Production of IgE

4) IgE binds to Mast cells (grenade ready to explode)

5) Repeat exposure: Allergen sticks to the IgE antibody (trigger)

6) Activation of Mast cell (explosion) --> release of histamine, leukotrienes, prostaglandins, and cytokines

7) Immediate reaction (minutes) --> Late reaction (2-8 hours)

Immediate hypersensitivity reaction of Type I allergic response

- Minutes after repeated exposure to allergen

- Release of Vasoactive amines (histamine) + Lipid mediators (Leukotrienes and prostaglandins)

- Swelling, sneezing, itching, etc

Late hypersensitivity reaction of Type I allergic response

- 2-8 hours after repeated exposure to allergen

- Release of Cytokines (immune signals)

- Causes lingering inflammation (stuffiness, swelling, and tissue damage)

Mast cell degranulation (breakdown)

- When Mast cells (or basophils) explode after being activated and release their chemical contents

- Causes a chain reaction that messes with different organs in the body

What 4 chemicals are released during mast cell degranulation?

- Histamines (biogenic amines)

- Cytokines (e.g., TNF)

- Lipid mediators (e.g., PAF, PGD2, LTC4)

- Enzymes ( e.g., tryptase)

During Mast cell degranulation in Type I hypersensitivity, what organ effects do histamines and lipid mediators cause?

- Vascular leak: blood vessels become leaky

- Bronchoconstriction: tightening of smooth muscles in your airways

- Intestinal hypermotility: overstimulation of the gut

During Mast cell degranulation in Type I hypersensitivity, what organ effects do cytokines and lipid mediators have on the immune system?

Inflammation: recruitment of other immune cells, causing redness, swelling, and pain (prolonging allergy symptoms)

During Mast cell degranulation in Type I hypersensitivity, what organ effects do enzymes cause?

Tissue remodeling: damage and change in tissue structure

What antibodies mediate Type II Hypersensitivity (Cytotoxic) reactions?

IgG or IgM antibodies

What does cytotoxic mean?

toxic to living cells

What system is involved in Type II hypersensitivity?

The complement system

What do Type II Hypersensitivity Cytotoxic reactions mainly target?

Cellular elements that are in close contact with circulating plasma (e.g., red blood cells)

What are the 3 outcomes of Type II Hypersensitivity Cytotoxic reactions?

- Opsonization and phagocytosis

- Inflammation (Complement-mediated)

- Antibody-mediated cellular dysfunction

What are 3 examples of Type II Hypersensitivity?

- Hemolytic anemia (opsonization and phagocytosis)

- Transfusion reactions (Complement-mediated Inflammation)

- Graves' disease (Antibody-mediated cellular dysfunction)

What are the 4 steps of Opsonization and Phagocytosis in Type II Hypersensitivity?

1) Cell marked as antigen (invader)

2) Opsonization: IgM or IgG antibodies stick to cellular antigen (mark the cell for destruction)

3) Complement (proteins) activated

4) Phagocytosis of cell antigen OR Lysis of cell antigen

What are the 3 steps of Complement-mediated inflammation in Type II Hypersensitivity?

1) Antibodies bind to the cell, triggering complement proteins

2) Complement proteins attract Neutrophils

3) Neutrophils release toxic enzymes and reactive oxygen intermediates

4) Causes Tissue injury and inflammation

What is Antibody-mediated cellular dysfunction in Type II Hypersensitivity?

Antibodies bind to cell receptors and either overstimulate or block/inhibit them, disrupting normal cell function without killing the cell

What antibodies mediate Type III Hypersensitivity (Immune Complex) reactions?

IgG or IgM antibodies

What system is involved in Type III hypersensitivity?

Complement system

What does Type III (Immune Complex) Hypersensitivity cause?

- Formation of Immune complexes (antigen-antibody complexes)

- Causes tissue damage

An example of Type III hypersensitivity is Serum Sickness. What is that?

- Disease caused by an antibody produced to horse or bovine serum used in antitoxins.

- Aggregates of IgG activate complement

An example of Type III hypersensitivity is the Arthus reaction. What is that?

Dermal inflammatory response, caused by the reaction of an antibody to an antigen in the skin

What are the 4 steps of Immune complex formation in Type III Hypersensitivity?

1) Antigen enters skin (e.g., vaccine)

2) Antigen and Antibody stick together --> Antigen-Antibody immune complex is formed

3) Immune complex sticks to tissue, activating complement proteins

4) Reactions of complement with the Immune complex attract Neutrophils

5) Neutrophils release lysosomal enzymes, causing inflammation

Type IV Hypersensitivity

Cell-mediated (T-cell-mediated) or delayed hypersensitivity

What immune cells (not antibodies) mediate Type IV Hypersensitivity?

T-cells (not antibodies)

What does Type IV Hypersensitivity cause?

T-cells get sensitized to a local antigen and trigger a reaction by releasing lymphokines and/or direct cytotoxicity (directly killing cells)

What is a common example of Type IV Hypersensitivity?

Contact sensitivity (poison ivy)

What are the 5 steps to a Type IV Hypersensitivity reaction when contact with poison ivy occurs?

1) Skin contact with poison ivy

2) Poison ivy chemicals (Pentadecacatechol molecules) bind to skin proteins

3) Dendritic cells show the poison ivy chemicals + skin proteins to T cells, which send it to Memory T cells

4) Upon re-exposure, Memory T cells release cytokines, macrophages, and cytotoxic T cells

5) Causes rashes, blisters, or lesions

Is the Type IV Hypersensitivity reaction immediate or delayed?

Delayed (takes 1-2 days)

What does the Mnemonic (ACID) for Hypersensitivity stand for?

A... Anaphylaxis reaction

C... Cytotoxic reaction

I... Immune complex-mediated reaction

D... Delayed type reaction

Autoimmunity

A breakdown in tolerance in which the immune system begins to recognize self-antigens as foreign and mistakenly attacks them. them

What are the tissues of the body affected by an Autoimmune attack?

- Thyroid

- Blood

- GI tract

- Nerves

- Lungs

- Skin

- Muscles

- Bones

- Brain

What is the Major Histocompatibility Complex (MHC)?

*A large genomic region or gene family found in most vertebrates, highly conserved

- aka HLA (Human Leukocyte Antigen)

On which chromosome in Humans is the MHC (HLA) found?

Chromosome 6

What is the MAIN function of MHC in immunity?

- Determination of "self" vs. "non-self"

- Direct T cell responsiveness

Why is the MHC important in the genome?

- The most gene-dense region of the mammalian genome

- Plays an important role in the immune system, autoimmunity, and reproductive success

Extreme Polymorphism

* Millions of alleles or variants exist; individuals inherit haplotypes

- Makes MHC highly variable across individuals

Class I MHC

- Expressed on ALL somatic cells;

- classic "transplantation antigens"

- genes: A, B, C, interact ONLY with T cytotoxic cells

Class II MHC

- Expressed on immune cells (B, T, macrophages, dendritic cells, thymus epithelium)

- Immune-associated (IA) antigens; important in immune regulation

- Cell-cell communication

- Genes: DP, DQ, DR (and others), interact only with T helper cells

Class III MHC

Complement

Which gender is more commonly affected by autoimmune diseases overall?

Females

Which autoimmune diseases are equal between the genders?

Psoriasis, Wegener's granulomatosis

What autoimmune disease is more common in males?

Ankylosing spondylitis

Mechanisms leading to Autoimmune disease: Original Insult

Drug-induced (hydralazine, a-methyldopa, procainamide) or virus-induced changes in cell surface antigens cause the production of anti-idiotypic antibodies

Mechanisms leading to Autoimmune disease: What does Cross-reactivity between exogenous antigens and self-antigens cause?

Similarities between exogenous antigens and self-antigens

Mechanisms leading to Autoimmune disease: How do Genetic Factors contribute to autoimmune disease?

- Usually familial, products of the MHC locus (e.g., HLA-DR2 in patients with SLE)

- Histocompatibility-complex-linked immune response genes (e.g., C4 & C2 genes)

- UV light

- X-chromosome mosaicism

Mechanisms leading to Autoimmune disease: What does Abnormal immunoregulation mean in autoimmune disease?

- B-cell overactivity

- Decreased T cell function

- Presence of spontaneously activated T & B cells

Mechanisms leading to Autoimmune disease: What is the Hidden Antigen theory?

A theory in which autoimmunity develops when previously hidden antigens are exposed to the immune system?

Mechanisms leading to Autoimmune disease: What role does Long noncoding RNA Xist play in autoimmunity?

- Silences 1 of 2 X chromosomes

- Makes ribonucleoprotein complex with unique binding proteins, some autoantigens

- Activates TLR pathways on innate immune system cells

What are the 2 main MHC classifications for autoimmune disease?

- MHC Class II-associated

- MHC Class I associated

Classification of Autoimmune Diseases: What are examples of MHC Class II-associated autoimmune diseases?

- Organ-specific: autoantibody directed against a single organ

- Systemic: systemic lupus erythematosus - variety of autoantibodies to DNA, cytoplasmic antigens, etc.

Classification of Autoimmune Diseases: What are examples of MHC Class I-associated autoimmune diseases?

- HLA-B27: spondyloarthropathies (ankylosing spondylitis, Reiter's syndrome)

- Psoriasis vulgaris (associated with HLA-B13, B16, B17)

Antibody-Mediated Autoimmune Diseases: What cells are targeted in Autoimmune Cytopenias (Anemia, Thrombocytopenia, Neutropenia)?

Erythrocyte, platelet, or neutrophil cell surface determinant

Antibody-Mediated Autoimmune Diseases: What antigen is targeted in Goodpasture's Syndrome?

Type IV Collagen

Antibody-Mediated Autoimmune Diseases: What receptor is targeted in Myasthenia Gravis?

Acetylcholine Receptor

Antibody-Mediated Autoimmune Diseases: What receptor is targeted in Hyperthyroidism?

Thyroid-stimulating hormone receptor

Antibody-Mediated Autoimmune Diseases: What receptor is targeted in insulin-resistant diabetes?

Insulin receptor

T-Cell Mediated Autoimmune Diseases: What is the T-cell target in Multiple Sclerosis?

Myelin basic protein

T-Cell Mediated Autoimmune Diseases: What is the T-cell target in Autoimmune thyroiditis?

Thyroid follicular epithelial cells

T-Cell Mediated Autoimmune Diseases: What are the T-cell targets in Insulin-dependent diabetes mellitus?

Pancreatic islet B cells, Insulin, Glutamic acid decarboxylase

T-Cell Mediated Autoimmune Diseases: Which virus is associated with T-cell attack on Viral myocarditis?

Coxsackie B virus

Human Proteins with Structural Homology to Human Pathogens: In Ankylosing Spondylitis/Reiter's Syndrome, which human protein is targeted, and which pathogen is associated?

HLA-B27; Klebsiella pneumoniae

Human Proteins with Structural Homology to Human Pathogens: In Rheumatoid arthritis, which human protein is targeted, and which pathogen is associated?

HLA-DR4, autoantigens; Epstein-Barr virus, Prevotella copri

Human Proteins with Structural Homology to Human Pathogens: In Insulin-dependent diabetes, which human protein is targeted, and which pathogen is associated?

Insulin receptor, HLA-DR, glutamate decarboxylase; Papillomavirus, Cytomegalovirus, coxsackievirus, P2-C enzyme

Human Proteins with Structural Homology to Human Pathogens: Rheumatic heart disease, which human protein is targeted, and which pathogen is associated?

Cardiac myosin; Group A Streptococci

How many gene loci are linked to Systemic Lupus Erythematosus (SLE), and which complement deficiencies are included?

- Over 100 gene loci with polymorphisms identified (including deficiencies in C1, C2, and C4)

Where is the genetic predisposition for SLE strongest?

- Genetic predisposition is greatest at the MHC locus (HLA-DR), X chromosome

What do Systemic Lupus Erythematosus (SLE) antibodies target?

- Nucleic Acids

- RBCs, WBCs, platelets

- Phospholipids

- Coagulation proteins

What type of hypersensitivity causes tissue damage in SLE?

Type III Hypersensitivity (Immune complex deposition)

What T-cell imbalance is seen in SLE?

- Imbalance between CD4+ T cell subtypes

What causes decreased or absent insulin in Diabetes Mellitus (Type 1)?

Destruction of Beta-cells in the pancreas

Is Type 1 Diabetes Mellitus polygenic or monogenic?

Polygenic with 20 different chromosomal regions identified

What genetic regions are linked to Type 1 Diabetes?

- MHC Class II (HLA-DR3-Dq2; HLA-DR4-DQ8)

- Insulin gene promoter

- CTLA-4 (cytotoxic T lymphocyte antigen-4)

- PTPN22 (protein tyrosine phosphatase non-receptor 22)

What are the Environmental factors contributing to Type 1 Diabetes Mellitus?

Viruses, Diet, and Gut Microbiota

What are the Immunologic factors of Diabetes Mellitus?

> Immune tolerance - failure of tolerance of T cells specific for

cell antigens

> Cellular immunity

> Humoral immunity

What % of Type 1 Diabetes patients have anti-islet cell antibodies?

90% of patients

Which antibodies target Beta-cell tyrosine phosphatases, and in what % of Type 1 Diabetes patients?

Anti-islet antigen(IA)-2a and IA-2b (phogrin) antibodies; 60-70% of patients

What % of Type 1 Diabetes patients have anti-glutamic acid decarboxylase (GAD) antibodies?

70% of patients

What % of Type 1 Diabetes patients have anti-insulin antibodies (before insulin treatment)?

92% of patients

Do anti-insulin and anti-islet autoantibodies mediate Beta-cell destruction?

NO-- but their coexistence strongly predicts future diabetes development

What kind of disorder is Rheumatoid Arthritis, and what does it primarily attack?

A chronic inflammatory disorder that attacks the joints

How many people worldwide are affected by Rheumatoid Arthritis?

Affects 17.6 million people worldwide

What % of the US population has Rheumatoid Arthritis, and what gender is more affected?

- 1% of the US population

- 3x more prevalent in females

What is produced in Rheumatoid Arthritis that can lead to the destruction of articular cartilage and adhesion of joints?

A nonsuppurative proliferative, inflammatory synovitis

What genetic factors are linked to Rheumatoid Arthritis?

> HLA-DRB1*, HLA-B, HLA-DQA1

> Non MHC regions - PTPN22, PADI4, TNFAIP3/A20, FOXP3, CRP, CTLA4, IL1RN, MTHFR

What environmental factors are linked to Rheumatoid Arthritis?

Cigarette smoke, silica exposure, periodontal disease, decreased gut microbiota diversity

What Antibodies are present in Rheumatoid Arthritis?

- Rheumatoid factors (antibody towards antigen-antibody complexes), predominantly IgM, found in 60-80% of patients

- Anti-citrullinated protein antibodies (ACPAs), predominantly IgG1 and IgA, are found in 2/3 of patients

- Anti-carbamylated protein antibodies, mainly IgG and IgA

- Anti-type II collagen and gp39 antibodies (cartilage-specific)

Why are Citrullinated proteins highly antigenic in Rheumatoid Arthritis?

They have a higher affinity for binding to HLA-DR

How can Citrullinated proteins induce inflammation in RA?

They can be internalized via TLR9, triggering an inflammatory phenotype in synoviocytes

Schematic of RA Injury: What are the main structural changes in bone, cartilage, and muscle in a Rheumatoid Arthritis joint compared to a normal joint?

- Bone loss

- Cartilage loss

- Muscle wasting

- Inflamed and hyperplastic synovial membrane

Which immune cells drive Rheumatoid Arthritis joint damage?

- T cells, B cells, macrophages, dendritic cells, osteoclasts

What are two key pathological damages of RA joints besides bone loss/cartilage loss?

- Extensive angiogenesis

- Antibody-driven inflammation

What are the main steps in the initiation and progression of RA?

1) In mucosa, risk factors cause proteins to change

2) In secondary lymphoid tissues, T cells and B cells make autoantibodies

3) Antibodies attack the body's own joint tissues

4) Immune cells flood the lining of the joint and release inflammatory cytokines

5) Cartilage and bones are destroyed, leading to Joint damage

What pathological changes occur in Multiple Sclerosis?

- Breakdown of the blood-brain barrier

- Multifocal inflammation

- Demyelination

- Oligodendrocyte loss

- Gliosis

- Axonal degeneration