Physiology & Pathophysiology of the Immune System (BIOMED- EXAM1 )

Describe the causative factor “intrinsic immune defects” of primary immunodeficiency ?

Inherited (congenital) genetic defects that compromise the normal development or function of the immune system. Such as:

• Pattern Recognition Receptors (PRRs),

• Toll-like receptor (TLR) deficiency

• Nucleotide-binding oligomerization domain (NOD) deficiency

What are Pattern Recognition Receptors (PRRs)?

Congenital defects affecting immune recognition

What is Toll-like Receptor (TLR) deficiency

TLR-5 can't recognize flagella

What is Nucleotide-binding oligomerization domain (NOD) deficiency

GI mucosal defects and predisposition to Crohn's disease

Describe the causative factor “B deficiencies” of primary immunodeficiency ?

• Due to low or absent antibody levels

• Starts in first 6-12 months of life

• Poor response to vaccination

  • Selective IgA deficiency (most common

  • X-linked hypogammaglobulinemia (Bruton’s agammaglobulinemia)

  • Hyper-IgM Syndrome

  • Common variable immunodeficiency (CVID)

Selective IgA deficiency

Recurrent lung, sinuses, GI infections, most common (B-cell deficiency)

X-linked hypogammaglobulinemia

Absence of B cells, deficiency in all immunoglobulins (B- cell deficiency)

Hyper IgM syndrome

Cannot change class of antibodies, excess of IgM but lack others. X-linked (B- cell deficency)

Common variable immunodeficiency

IgG deficiency later in life (B-cell deficiency)

Describe the causative factor “T deficiencies” of primary immunodeficiency ?

• Most severe

• Are central to many immune responses

• Starts in first 6-12 months of life

• Susceptible to a broad range of infections

  • Wiskott-Aldrich

  • Ataxia-Telangiectasia

  • Thymic aplasia (DiGeorge syndrome)

  • Chronic mucocutaneous candidiasis

Wiskott-Aldrich syndrome

X-linked mutation to WAS gene, pyogenic infections (T-cell deficiency)

Ataxia-telangiectasia

Defective ATM gene, low IgA (T-cell deficiency)

Thymic aplasia (DiGeorge)

Chromosome 22 deletion, thymus and parathyroid glands fail to develop, absence of T cells (T-cell deficiency)

Chronic mucocutaneous candidiasis

IL-17 receptor deficiency, deficient T cell response to candida (T-cell deficiency)

Severe Combined Immunodeficiency Syndrome (SCID)

X linked, lack of B and T cells, low immunoglobulin levels, bubble boy

Describe the causative factor “Leukocyte adhesion deficiencies” of primary immunodeficiency ?

• Autosomal recessive inheritance

• Defective adhesion protein LFA 1

• Manifests as severe pyogenic infections early in life; extremely high leukocyte count

  • Chronic Granulomatous Disease (CGD)

  • Chédiak-Higashi Syndrome

  • Cyclic Neutropenia

Chronic Granulomatous Disease

X linked, can trap organism but cannot kill it, leads to granules

Chediak-Higashi syndrome

Autosomal recessive, LYST gene mutation, lysosomes cannot lyse stuff

Cyclic neutropenia

Autosomal dominant, ELANE gene mutation, low neutrophils every 21 days

Describe the causative factor “complement deficiencies” of primary immunodeficiency ?

A lack of specific complement proteins (such as C3), which hinders the complement cascade needed to clear infections.

• C3 Deficiency

• C5, 6, 7, 8, 9

• C1 esterase inhibitor deficiency

• Autoimmune disease

C3 Deficiency

Increased susceptibility to encapsulated organisms

C5, 6, 7, 8, 9 deficiency

No MAC, susceptible to Neisseria

C1 esterase inhibitor deficiency

Hereditary angioedema

Describe Immune tolerance

Lack of response to antigen, avoiding attacking self

What are factors that determine tolerance

• Immune system maturity

• Antigen structure

• Cross reactivity

• Inflammatory signals

Immune system maturity

Immature systems learn to tolerate better (tolerance)

Antigen structure

Simple or self-like structures can be better tolerated

Cross-reactivity

Tolerance is maintained or autoimmunity occurs

Inflammatory signals

No signals lead to more tolerance; inflammatory signals lead to less tolerance

Describe central tolerance (thymic)

Tolerance to self-antigens that is acquired within the thymus. It involves "positive selection" (keeping T cells that recognize MHC receptors) and "negative selection" (eliminating T cells that react strongly to self-antigens).

What is positive selection in reference to T cell tolerance

• selects for T cells with a T cell receptor and CD4/CD8 receptor (double positive) that recognize MHC I/MHC II

  • “Rule of eight”

What is the Rule of eight

• Class II MHC binds to CD4-positive T cells → (2 x 4 = 8)

• Class I MHC binds to CD8-positive T cells → (1 x 8 = 8)

What is negative selection in reference to T cell tolerance

eliminates T cells that react strongly to self antigens encountered in the thymus

Describe Peripheral Tolerance (Post-thymic)

Tolerance acquired outside the thymus. It acts as a necessary backup mechanism to control self-reactive T cells that encounter self-antigens which were not present in the thymus.

• Anergic

• T regulatory (Tregs)

Define Anergic

Unresponsive (Lack of T cell co-stimulation)

Define T regulatory cell (Tregs)

suppresses T cell activation or induce apoptosis

Describe B-cell tolerance

• Tolerance developed through negative selection in the bone marrow

• Fails tolerance test

  • Antibody receptor editing

    • unique to B cells only

  • Apoptosis

  • Anergy

Loss of self tolerance (LoT) leads to….

autoimmune diseases

What are the types of immune response to LoT

• Antibody to receptors

• Antibody to cell components

• T-cell mediated

Genetic predisposition (LoT)

Involves human leukocyte antigens (HLA).

HLA-DR (LoT)

Associated with diabetes

HLA-B27 (LoT)

Associated with ankylosing spondylitis

Autoimmune diseases prevalence in women (LoT)

90% occur in women, estrogen main cause

Molecular mimicry (LoT)

Infectious agent induces immune response that cross-reacts with self-proteins.

Graves disease

Involves TSH receptor, autoimmune disease

Myasthenia gravis

Involves acetylcholine receptor, autoimmune disease

Insulin dependent diabetes

Involves islet cells, autoimmune disease

Rheumatic fever

Affects heart and joint tissue, autoimmune disease

Celiac disease

Enterocytes destroyed by cytotoxic T cells, autoimmune disease

Define Antibody receptor editing

gets rid of self-reacting cells by creating a slightly different antibody with a slightly different light chain with different recognition

• Unique to B cells ONLY

Define Anergy

developmental arrest/unresponsive

Define Autograft

Transfer of an individual’s own tissue to another body site

Define Isograft (syngeneic graft)

Transfer of tissue between genetically identical individuals (identical twins)

Define Allograft

graft between genetically different members of the same species

Define Xenograft

transfer of tissue between different species

Define a "Host vs. graft" response in transplantation.

The recipient's immune system identifies the transplanted tissue as foreign and attacks it.

• Hyper acute rejection

• Acute rejection

• Chronic rejection

Graft vs Host reaction (GVH)

• In allogenic stem cell transplants, donor T cells attack the recipient’s tissues a organ dysfunction

• Risk factors:

  • HLA mismatch

  • Unrelated donor

  • Older age of donor/recipient

• Symptoms: often affects skin and GI tract

  • Severe body rash

  • Oral ulcers

  • Nausea, vomiting, diarrhea, hepatitis

Hyper acute rejection

Occurs minutes to hours after transplant, due to ABO incompatibility

Acute rejection

T cell mediated rejection occurring 2 weeks post-transplant due to HLA mismatch

Chronic rejection

Gradual loss of function occurring months to years, persistent acute rejection

Direct pathway

HLA mismatch where host cytotoxic T cells recognize graft cells as foreign, causing acute rejection

Indirect pathway

Chronic rejection where donor proteins are presented by host APC

Major histocompatibility complex (HMC)

Set of genes that encode major antigens (human leukocyte antigens-HLA) and is important in organ transplantation. MOST crucial for matching donors and recipients for transplants, chromosome 6

Minor histocompatibility complex (MHC)

Encoded by genes at sites other than the HLA locus. Typically induces a weak immune response→ slow rejection of a transplant. Difficult to predict rejection based on minor antigens

Describe Type I hypersensitivity and the clinical manifestations

• immediate hypersensitivity

• IgE mediated, response to allergen, mild to life threatening, mast cell degranulation.

• Atopy

• Atopic triad

Clinical manifestations

• Systemic anaphylaxis

• Rash

• Urticaria (hives)

• Rhinitis

• Conjunctivitis

• Wheezing (asthma)

• Edema

Atopic Triad

Asthma, eczema, allergies

Define Atopy

genetic tendency to develop allergic diseases

Describe Type II hypersensitivity and the clinical manifestations

• Cytotoxic hypersensitivity

• Occurs when antibody directed at antigens of the cell membrane activates complement →cell death

• IgG or IgM mediated

• Antigen bound to cell membranes

Clinical manifestations:

• Hemolytic anemia

• ABO transfusion reactions

• Rh hemolytic disease

• Infections (Mycoplasma pneumoniae

Hemolytic transfusion reaction

Type 2 Hypersensitive reaction

Hemolytic disease of the newborn

Rh negative mother has Rh positive fetus, mother can become sensitized and attack second Rh positive fetus. Type II reaction

Cold agglutinin disease

IgM binds in cold, causes complement to bind. Type II reaction

Describe Type III hypersensitivity and the clinical manifestations

• Immune complex hypersensitivity

• Occurs when antigen-antibody complexes induce an inflammatory response in tissues

• Antigens are freely circulating

• Antigens-Antibodies form large complexes

Clinical manifestations

• Arthus reaction

• Serum sickness

• Immune complex deposition disorders (lupus

Arthus reaction

localized inflammation caused by immune complex deposition in vessel walls, alveoli. Type III hypersensitivity

serum sickness

systemic inflammatory response to the presence of immune complexes deposited in many areas of the body due to injection of foreign serum. Type III hypersensitivity

Lupus

Autoantibodies, complexes deposit everywhere. Type III hypersensitivity

Describe Type IV hypersensitivity and the clinical manifestations

• Delayed hypersensitivity

• Caused by T lymphocytes, not antibody

• Delayed response

  • Occurs hours to days after contact with antigen and lasts for days

Clinical manifestations:

• Poison ivy

• Tuberculin skin test (PPD)

• Contact hypersensitivity

  • Nickel, soaps, cosmetics, neomycin

• Erythema multiforme

• Stevens-Johnson Syndrome

• Toxic Epidermal Necrolysis

contact dermatitis

T cells recognize antigen. Type IV hypersensitivity

Tuberculin skin test

Macrophages show up due to memory T cell response. Type IV hypersensitivity

Severe reactions in Type IV

Caused by cytotoxic T cells attacking skin - EM, SJS, TEN.