Immunodeficency and Autoimmune Disorders

Question 1

Digeorge Syndrome

Answer 1

22q11 microdeletion leads to failure to develop 3rd and 4th pharyngeal pouch so dont get THYMUS (t-cell deficiency), parathyroids (hypocalcemia), and also get abnormalities of heart, great vessels and face.
No t-cells so cant fight viral and fungal infections

Question 2

Sever Combined Immunodeficiency Syndrome (SCID)

Answer 2

Defective cell mediated (T-Cell) and humoral (b-Cell) immunity
Etiologies include
1) Cytokine Receptor defect = cytokines typically needed for proliferation and maturation of B-Cells and T-Cells
2) Adensoine Deamine Defficency = ADA deamnites adenosine and deoxyadenosine. Without these molecules build up and are toxic to lymphocytes
3) MHC class II deficiency = MHC II is necessary for CD4+ helper T-Cell activation and cytokine production
Characterized by susceptibility to fungal, viral, bacterial and protozoal infections
Dont give live vaccines. Need to isolate baby until stem cell transplantation

Question 3

Cytokine Receptor defect

Answer 3

SCID = cytokines typically needed for proliferation and maturation of B-Cells and T-Cells
Characterized by susceptibility to fungal, viral, bacterial and protozoal infections
Dont give live vaccines. Need to isolate baby until stem cell transplantation

Question 4

Adensoine Deamine Defficency

Answer 4

SCID = = ADA deamnites adenosine and deoxyadenosine. Without these molecules build up and are toxic to lymphocytes
Characterized by susceptibility to fungal, viral, bacterial and protozoal infections
Dont give live vaccines. Need to isolate baby until stem cell transplantation

Question 5

MHC class II deficiency

Answer 5

SCID = = MHC II is necessary for CD4+ helper T-Cell activation and cytokine production
Characterized by susceptibility to fungal, viral, bacterial and protozoal infections
Dont give live vaccines. Need to isolate baby until stem cell transplantation

Question 6

X-Linked Agammaglobulinemia

Answer 6

lack of Ig due to disordered B-Cell maturation as a result of mutated Bruton Tyrosine kinase (X-linked)
Presents after 6 months of life with recurrent bacterial, enterovirus (polio and coxi), and Giradia lamblia infections but mothers Ig protective for 1st 6 months.
Avoid live vaccines (polio)

Question 7

Common Variable Immunodeficiency

Answer 7

Low Ig due to B-Cell or helper T-Cell defects
increased risk for bacterial, enterovirus (polio and coxi), and Giradia lamblia infections, as well as autoimmune disease and lymphoma

Question 8

IgA Deficiency

Answer 8

Low serum and mucosal IgA
MOST COMMON Ig deficiency
Increaed risk for mucosal infection, especially viral
Usually asymptomatic
Can also see Celiac disease with low IgA

Question 9

Hyper IgM Syndrome

Answer 9

Elevated IgM due to mutated CD40L of helper T-Cell or CD40 receptor of B-Cells. Without CD40 cant make or bind IL4 and IL5 which are cytokines necessary for Ig calss switching. Therefore get high IgM and low IgA,G,E
Get pyrogenic infections due to poor opsonization, especailly at MUCOSAL sites

Question 10

Wiskott-Aldrich Syndrome

Answer 10

triad of thrombocytopenia, eczema, and reccurent infections ( deffective humoral and cellular immunity)
bleeding is major cause of death
Due to mutation is WASP gene = x linked

Question 11

C5-9 Deficiencies

Answer 11

Increased risk for Neisseria infection (N gonorrhea and meningitidis

Question 12

C1 inhibitor deficiency

Answer 12

get overactivation of complement that leads to increased vasodilation and vasuclar permeability. Get hereditary angioedema (edema of skin (PERIORBITAL) and mucosal surfaces)

Question 13

Progression of T cell development and central tolerance

Answer 13

stem cells in bone marrow, then travel to thymus as double positive, if pass positive selection (can bind to MHC II) then become single positive, single positive undergo negative selection (don’t bind self antigen presented by dendritic cells and medullary epithelial cells, occurs in medulla of thymus), then exit as naive mature T-Cells

Question 14

Autimmune Polyendocrine Syndrome

Answer 14

Medullary epithelial need AIRE to express self antigens. If missing then don’t express self antigen and get a failure in negative selection and T-Cells that are self reactive. As a result get Autimmune Polyendocrine Syndrome characterized by

1) hypoparathyroidism
2) Adrenal failure
3) repeated candida infections of skin and mucosa

Question 15

Progression of B cell Development

Answer 15

Stem cells in bone marrow become immature Ig then undergo negative selection where RAGs edit light chains to try and make succesful light chain, if fail then then they die, if pass they exit as naive mature B cells

Question 16

Peripheral Tolerance

Answer 16

1st signal is typically TCR of CD4 recognizes MHCII of dendrite. Then need dendrite to express B7 and interact with CD28 of T cell. this is the second signal. If no 2nd signal get anergy. If binds MHCII with self antigen chronically then T-Cell undergoes apoptosis by expressing FAS ligand that interacts with CD95?FAS receptor on same T-cell which leads to cell death. FASL can also bind other CD4 T-Cells’ CD95 and cause them to die

Question 17

Autimmune Lymphoproliferative Syndrome

Answer 17

mutations in FAS apoptosis pathway. Lose FASL or FASR/CD95 or caspase 10 so T-cells dont die and make IgG against cells in blood leading to anemia or thrombocytopenia and get proliferation of self reactive lymphocytes and get lymphadenopathy and hepatosplenomegally. Can eventually progress to lymphoma

Question 18

Regulatory T-Cells

Answer 18

CD4+ and suppress immune responses by expressing CTL4 that binds B7 to decrease 2nd signal
Also secrete IL10 which inhibits dendritic cells production of B7
Also secrete TGFbeta to inhibit activation of macrophages
Are CD4+, CD25+, and FOXP3 (needed for development and maintenance

Question 19

Systemic Lupus Erythematous Sunlight Theory

Answer 19

Sunlight hits keratinocytes and causes them to apoptose. DNA is released and self reactive B lymphocyte sees nuclear material and makes Ab against it nuclear antigens.
Next time get UV damage, nuclear material is released, AB binds Ag at low levels, dendritic cells take up ABAg complexes and can activate denritic cell’s TLR and amplify the immune response by further activating B cells to make more Ab, so get increased AbAg complexes with subsequent UV damage.

Supported by high SLE incidence in Complement deficiencies (C1q, C4, and especially C2)

Question 20

Classic Findings of SLE

Answer 20

In general it is a Type III hypersensitivity rxn (AgAb complexes)

1. Fever, weight loss, fatigue, lymphadenopathy, and Raynaud phenomenon
2. Malar ‘butterfly’ rash or discoid rash, especially upon exposure to sunlight
3. Oral or nasopharyngeal ulcers (usually painless)
4. Arthritis (usually involving >2 joints)
5. Serositis (pleuritis and pericarditis)
6. Psychosis or seizures
7. Renal damage
   i. Diffuse proliferative glomerulonephritis is the most common and most severe form of injury.
   ii. Other patterns of injury (e.g.,membranous glomerulonephritis) also occur.
8. Anemia, thrombocytopenia, or leukopenia (type II HSR)
9. Libman‐Sacks endocarditis (small sterile deposits on BOTH side of the mitral valve)
10. Antinuclear antibody (ANA; sensitive, but not specific)
11. Anti‐dsDNA or anti‐Sm antibodies (highly specific)

Question 21

Drug Induced SLE

Answer 21

Antihistone antibody is noted.
Caused by Hydralazine, procainamide, and isoniazid
Rarely involves kindey or CNS and resolves with removal of drug

Question 22

Antiphospholipid Antibody Syndrome

Answer 22

associated with SLE in 30% of cases. Get antibody to proteins bound to phospholipids.
Anticardiolipin leads to false postive for syphilis tests
Lupus Anticoagulant leads to falsely elevated PTT (which is especially false cus they are actually hypercoaguable)
Can get arterial and venous thrombosis (DVT, hepatic vein thrombosis, and palcental thrombosis (multiple misscariages!!!)
Person needs to be on anticoagulants for life

Question 23

Major complications of SLE

Answer 23

Death by renal failure or infection.

Also get accelerated Coronary Atherosclerosis

Question 24

Sjogren Syndrome

Answer 24

Autimmune destruction of lacrimal and salivary glands.
Lymphocyte mediated damage (type IV hypersensitivity) with fribrosis)
Classically presents as dry eyes, dry mouth (xerostomia) and recurrent dental carries in an older woman
“cant chew a cracker and have dirt in eye”
ANA and anti-ribonucleoprotein (anti-SS-A/Ro and Anti SS-B/La)
anti SSA can cross placenta and cause neonatal lupus and congenital heart block
Often assoicated with other autoimmune disorders such as rheumatoid arthritis (see rheumatoid factor)
At increased risk for B-Cell (marginal zone) lymphoma which presents as enlargement of parotid gland

Question 25

Scleroderma/Systemic Sclerosis

Answer 25

Autoimmune disease characterized by activation of fibroblasts and deposition of collagen (Fibrosis)

Question 26

Localized Scleroderma

Answer 26

Autoimmune disease characterized by activation of fibroblasts and deposition of collagen (Fibrosis) that only involves the skin.
Highly associated with Antibodies against DNA topoisomerase II

Question 27

Systemic Sclerosis

Limited vs diffuse

Answer 27

Autoimmune disease characterized by activation of fibroblasts and deposition of collagen (Fibrosis) that involves both skin and visceral organs

Limited = limited involvement of skin (mostly HANDS, face and neck) with late visceral involvement.
CREST Syndrome = Calcinosis/anti-Centromere Antibodies, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly (wrinkles of hand disappear), Telangiectasias of skin

Diffuse = involves skin and any visceral organ (especially GI, but also vessels, lungs, heart, and kidneys. Usually have DNA topoisomerase I antibodies

Question 28

Mixed Connective Tissue Disease

Answer 28

Autoimmune mediated tissue damage with mixed features of SLE, systemic sclerosis, and polymyositis (inflmation of joints nad muscles)
See serum antibodies against U1 ribonucleoprotein.