Med I: Autoimmunity and Immunodeficiency

Sensitization

Step 1 of hypersensitivity

• Mentioned through hypersensitivites

  • Phase where immune system recognizes something as non self and starts process to form response/memory against it

  • All hypersensitivies need a stage of sensitization in order for that robust response later

    ► Step 1 is contact (example allergen)

    ► Step 2 is T helper cell recognizes antigen presented to them

    ► Step 3 – Bcells are triggers to make the anitbodies needed (ex IgE in type 1)

    ► Step 4 – cells are primed to react if foreigner ever re-circulates in that

    body/future encounter

Tolerance

guard against autoimmune

• Feature of adaptive immunity

• Defined as the lack of responsiveness to a specific antigen that is capable of eliciting an immune response

  • Role of the immune system to remain inactive during encounters with harmless microbes or environmental substances

  • For example: antigens that could cause transfusion reactions in another individual but in your own body, do not cause an autoimmune reaction

• Immune tolerance to self is supposed to develop. When it

  does not, we see autoimmune disease

Difference between central and peripheral tolerance

Central Tolerance

• Occurs during the development of immune cells in primary lymphoid organs L

• Location: Thymus for Tcells and bone marrow for B cells

• Apoptosis in negative selection

• B cells can change their receptors to not react

• Elimination of autoreactive

• immune cells to protect the self

• Cells being checked → reacting on self (?) apoptosis

Peripheral tolerance

• Location: Operate in peripheral tissues after immune cells have matured and entered circulation

• Act as a checkpoint for any autoreactive cells that have made it into the periphery

• Ensures they are deleted or become anergic (unresponsive) to self antigen

• Tregs play a role here (produce antiinflam cytokines)

Risk factors of autoimmune disease

1. Genetic

• alleles of HLA-DR gene (delay markers) increase risk of RA (rheumatoid arthritis)

2. Hormonal

• 90% of autoimmune disease is in women

3. Environmental

• Infections – bacteria or viruses posses cross reacting antigen (bad symp)

• Drugs and heavy metals

Mechanisms of autoimmune disease

1. Molecular mimicry

Environmental trigger (infection,etc) resembles a component of "self" leading to an immune attack on self

Example – Rheumatic fever

2. Alteration of Normal Proteins

Drugs can bind to normal proteins making them immunogenic

Example – SLE induced by the drug procainamide

3. Release of sequestered antigens

Example – sunlight in SLE rash

4. Epitope spreading - occurs after chronic viral infection of inflammation

Example type 1 diabetes

Multiple sclerosis

Involves primarily one type of cell or organ (damage is white matter in brain)

Autoreactive T cells and activated macrophages lead to demyelination of the brain's white matter

Thought to be triggered by viral infection leading to stimulation of autoreactive T cells

Detected via MRI – plaques in the white matter

Detected by laboratory testing of spinal fluid – oligoclonal bands of IgG detected

Immunosuppresive drugs target CD20 (B cell marker) to prevent flares

Chronic thyroiditis

Involves primarily one type of cell or organ - thyroid

Hashimoto's thyroiditis

Antibodies form against (cause cell death) thyroglobulin and thyroid peroxidase and lead to fibrosis of the thyroid gland

Treatment focused on replacing thyroid hormone

Anemias, thrombocytopenias, and granulocytopenias (Hemopathology)

Individually involves primarily one type of cell or organ

Attachment of autoantibodies to cell surfaces and subsequent cell destruction

Immune thrombocytopenic purpura (ITP) caused by antibodies directed against platelets

Autoimmune hemolytic anemia caused by drugs that lead to autoantibodies directed against RBCs resulting in hemolysis of erythrocytes

Pernicious anemia – caused by antibodies to intrinsic factor (released by stomach cells). Leads to the loss of B12 absorption and so requires B12 supplementation

Type 1 diabetes mellitus

Individually involves primarily one type of cell or organ

Autoreactive T cells destroy islet cells found in the pancreas

• Islet cells produce insulin

Mechanisms against cancer

• Immune response of host against cancer cells directed by T cells

  • Cells that infiltrate tumors

    • NK cells – kill directly or can react to a cell bound to antibody

    • CD8-positive cytotoxic T cells

    • Macrophages activated by antigen specific Th-1 cells and cytokines

• Tumor cells

  • Decrease expression of MHC tumor associated antigens

  • Release soluble factors that take advantage of the host and recruit the host Treg cells

  • Expression of cell surface molecules that can inhibit functions of NK and cytotoxic T cells

  • Can actually push T cells into a dormant state by overwhelming them

    • T cell exhaustion

  • Create their own antibodies that either kill host cells or block the ability of host to recognize them allowing tumor to grow 8/16/2026 120

Immunodeficiency

Characteristics

• Components: Bcells, (antibody), Tcells. Complement, and Phagocyytes

• Most are acquired and caused by immunosuppressive medications

• Others are congenital but rare

Congenital versus acquired immunodeficiencies

(no need to memorize)

Combined B and T Cell Disorders

Severe Combined Immunodeficiency (SCID)

• Specific deficiency: Deficiency of both B‑cell and T‑cell function

• Molecular defect: Various mutations — defective IL‑2 receptor, defective recombinases, defective kinases, absence of class II MHC proteins, or ADA/PNP deficiency

• Clinical features: Bacterial, viral, fungal, and protozoal infections

T‑Cell Disorders

Thymic Aplasia (DiGeorge’s Syndrome)

• Specific deficiency: Absence of T cells; suppressed antibody responses

• Molecular defect: Defective development of pharyngeal pouches; associated with chromosome 22 deletions

• Clinical features: Viral, fungal, protozoal infections; tetany due to hypoparathyroidism

Chronic Mucocutaneous Candidiasis

• Specific deficiency: Deficient T‑cell response to Candida

• Molecular defect: IL‑17 and IL‑17 receptor deficiencies

• Clinical features: Skin and mucous membrane infections with Candida

B‑Cell Disorders

X‑Linked (Bruton’s) Agammaglobulinemia

• Specific deficiency: Absence of B cells; very low immunoglobulin levels

• Molecular defect: Mutant tyrosine kinase

• Clinical features: Recurrent bacterial infections, especially respiratory, caused by pyogenic bacteria such as pneumococci

Selective IgA Deficiency

• Specific deficiency: Very low IgA levels

• Molecular defect: Failure of heavy‑chain gene switching

• Clinical features: Recurrent infections of sinuses and lungs caused by pyogenic bacteria

Complement Deficiencies

C3b Deficiency

• Specific deficiency: Insufficient C3

• Molecular defect: Unknown

• Clinical features: Pyogenic infections, especially with Staphylococcus aureus

C6, C7, C8 Deficiency

• Specific deficiency: Insufficient C6, C7, C8

• Molecular defect: Unknown

• Clinical features: Neisseria infections

Phagocyte Disorders

Chronic Granulomatous Disease

• Specific deficiency: Defective bactericidal activity due to absent oxidative burst

• Molecular defect: Deficient NADPH oxidase activity

• Clinical features: Pyogenic infections, especially with Staphylococcus aureus and Aspergillus

Alloimmunity (blood donation)

Defined as a type of immunity that produces an immune response that attacks tissues or cells from a member of the same species

Body does not recognize as self

Example is transfusing patient with another human’s cells (pRBCs) leading to a transfusion reaction

Transplants

Recipients of grafts or transplanted organs, depend on the similarity between recipient and donor

► Autograft – individual’s own tissue transplanted to another site in the body

► Syngeneic graft – transfer of tissue between genetically identical (twins)

► Xenograft – transfer of tissues between different species

► Allograft – genetically different members of same species

• Requires immunosuppressive drugs for recipient to successfully “accept”

• Depends on the difference between donor and recipient at MHC site

Allograft rejection

Allograft transplants rely on immunosuppression to prevent rejection

Require HLA matching

Acute allograft rejection – 11-14 days after vascularization of the graft, blood flow reduced and immune cells infiltrate the graft. Leads to necrosis and rejection

Rejection is caused by a T cell mediated reaction

• Antibodies may play a role and contribute as well (humoral)

Cancer cells

Characteristics

• Similar to healthy cells and contain elements that are similar to “self”

• Display the same major human leukocyte antigen (HLA) and minor histocompatibility proteins

• Neoplastic cells will develop tumor associated antigens (TAAs) and be recognized as “nonself” by the body