Web viewSAP = SLAM Associated Protein. Absence of effective T-Cell Control for EBV Infection. ... 2NRTIs + a PI/NNRTI/II. Nucleoside and Nucleotide Reverse Transcriptase

HYPERSENSITIVITIES

All Hypersensitivities: o All Hypersensitivity reactions are NOT the Primary Immune Response.o Allergens must contain peptides that bind to host MHC Class II Molecules.o Hypersensitivities involving IgG can be transferred to the fetus via Passive Transfer.

Definitions: o Allergens: low molecular weight, contain peptide for MCH Class IIo Anaphylaxis: shock; BP drops suddenly, airways narrowo Atopy: genetic tendency for allergies.

Type I HSR: IgE Mediated o Immune Reactant: IgEo Antigen: Solubleo Effector Mechanism: Mast Cell Activationo Examples: Allergic Rhinitis, Allergic Asthma, Eczema, Systemic Anaphylaxis

Inhaled: Plant Pollen, Dander, Mold, Feces of Mites Ingested: Food, Orally-Administered Drugs

o Time: Immediate, Seconds, Minutes Resolves in 2 Hours.o Hypotheses:

Hygiene Hypothesis: a hypothesis that states that a lack of early childhood exposure to infectious agents, symbiotic microorganisms (such as the gut flora or probiotics), and parasites increases susceptibility to allergic diseases by suppressing the natural development of the immune system.

Hygiene Hypothesis = Genetic Susceptibility + Environment Genetic Susceptibility: Caused by Polymorphisms in MHCII, TLR, or

Cytokines. Another Hypothesis: In more advanced countries, we do not have bad parasites to

fight off, so our Immune System starts fighting off the smaller antigens that it shouldn’t, causing Hypersensitivity.

o Type I Hypersensitivity Mechanism: T-Cell Activation: STAT3, Prostaglandins, PDGER2 Th2: GATA2, IL-4, IL-13.

In Type I HSR, you have too much Th2 and not enough Th1. Th1 is needed for a healthy response.

IgE: Heavily glycosylated binding sites for FcER on Mast Cells Activation of Mast Cells.

Mast Cells: Activated in the Early Phase

o Reside in tissue Cause Diarrhea, Swelling, Mucus Secretion, Increase in Blow Flow, Increased

Permeability, Hypotension Remodel CT Matrix (carboxypeptidase and Tryptase) Toxic Mediators: Histamine/Heparin

Eosinophils: Activated in the Late Phase Th2 secretes IL-5, Eotaxin, and IgE in the Late Phase. Tissue Damage due to an Allgergic Reaction causes CXCL8 Secretions. IL-3, IL-5, and GM-CSF stimulate Eosinophil Production

You also start making Memory Th2 Cellso Sensitization:

First Exposure with Allergen Example: DERP (respiratory allergen)

DERP1 enters mucosa Dendritic Cell picks it up and carries it to the Lymph Node Th2 Cell is activated and induces a B-Cell Class Switch to IgE IgE binds to Mast Cell Receptors No Symptoms

** Class Switching needs T-Cell Help (CD4+) ** ** C5a sensitizes Mast Cells **

o Elicitation: Second Exposure with Allergen Example: DERP (respiratory allergen)

DERP1 enters mucosa for the Second Time Allergen is recognized by the IgE on Mast Cells Degranulation of Mast Cells Allergic Reaction

Wheel & Flare: Happens within minutes Wheel: fluid filled itchy bump – edema Flare: redness – erythema

o Treatment: Inhibit Mediators (Antihistamine) Anti-inflammatory Medication (Corticosteroids) Induce Tregs (Desensitization Therapy) Prevent IgE Binding to Mast Cells (Anti-IgE Antibodies)

o Mode of Entry: Transmucosally (Inhaled)

Most common Favors IgE Production and Th2 Response Examples:

o Bronchial Asthmao Hay Fever: large particles, limited to upper airwayso Extrinsic Asthma: smaller particles, alveolar space

Most common type Unknown Mechanism for Intrinsic

o Atopic Dermatitis (Eczema)o Tests:

Wheel and Flare Test: Allergen-Induced release of Histamine by Mast Cells causes Localized

Swelling. Read in minutes – skin test

RAST (Radioallergosorbent Test) Purified allergen is on a stick; it is immersed in the patient’s serum. Does the Patient have antibody to the allergen? Add Anti-human Antibodies (IgE Isotype Specific) Detect IgE Antibodies to the Antigen presented ELISA Version:

o 1st Layer: Allergeno Middle Layer: Patient’s Serum IgEo 3rd Layer: Anti-human Anti IgE

Type II HSR: Ab-Mediated o Immune Reactant: IgGo Antigen: Cell-Surface Receptor

Antibody alters signalingo Effector Mechanism: Complement, (Classical) Phagocytosis, NK Cellso Examples: Drug Allergies (Penicillin), Chronic Urticaria

Blood Transfusions, Erythroblast Fetalis, Hemolytic Anemiao Time: Intermediateo Cytotoxic Versus Non-Cytotoxic:

Type II HSR Cytotoxic Diseases: Goodpasture Syndrome: anti-collagen IV, smooth linear deposition pattern. Rheumatic Fever: cross-reactivity with myocardium, molecular mimicry. Penicillin Reaction: modifies cell membrane proteins into foreign epitopes Thrombocytopenic Purpura: antibodies against platelets Autoimmune Hemolytic Anemia (HDNB):

o RhD negative mothero RhD positive babyo Maternal Anti-RB ab’s cross the Placenta and attack the RH+ Fetus

RBC’so First baby = no reaction, sensitizationo Second baby = Erythroblastosis fetalis

Rhogam: IgG anti-RhD forms complex that inactivates the B-Cells that bind to the fetal blood no sensitization of the mother

ABO Antigens (blood) o O: no A or B Glycosyltransferaseso A: no B Glycosyltransferaseso B: no A Glycosyltransferaseso AB: has both A and B Glycosyltransferaseso Recognized by IgM made by normal flora

Hyperacute Rejection Type II HSR Non-Cytotoxic Diseases:

Myasthenia Gravis: Antibody inhibits binding of neurotransmitter to receptor Antagonist

Grave’s Disease: Antibody stimulates the TSH Receptor within the hormone Agonist

Type II Diabetes: antibodies to Insulin Receptor block it Hyperglycemia Pernicious Anemia: antibodies to Intrinsic Factor Low B12

Type III HSR: Immune Disease Complex o Immune Reactant: IgGo Antigen: Soluble Antigeno Effector Mechanism: Complement, (Classical) Phagocytosis, Neutrophils

Tissues are damaged because they are innocent bystanders to the destruction by the immune complex.

RBC’s transport IC’s to the spleen or liver for disposal. The problem occurs when IC’s are not properly removed from circulation, causing an infiltration of neutrophils (IL-8)

o Time: Intermediateo Examples:

Serum Sickness – giving horse anti-snake venom. Systemic = Transient Human antibody binding to venom and horse antibody binding to human

antibody Systemic Lupus Erythematosus Arthus Reaction –

Cutaneous Skin Test – Visualized in the Skin Mast cells degranulate but it takes 1-2 hours (not minutes like in Type I) Farmer’s Lung: Hypersensitivity Pneumonitis (HP)

Post-Streptococcal Glomerulonephritis – lumpy and bumpy

Type IV HSR: Cell-Mediated o Immune Reactant: Th1 (CD4)o Antigen: Soluble Antigen, Cell-Associated Antigeno Effector Mechanism: Macrophage Activation, CTL Activationo Time: Delayed (start 48 hours after exposure)o Cytokines:

INFY/TNFa: Local Tissue Destruction GM-CSF/IL-3: Monocyte Production IL-8: Chemokine mCAF: Macroattractor

o Sensitization: Effector Th1 Cells and Memory Cells (Macro=APC)

o Elicitation: Re-exposure causes Th1 to produce Cytokines

Memory T-Cells release Cytokines (Macro=Effector Cells) Release Lytic Enzymes = Hydrolases, Oxidases = Tissue Damage

o Examples: Granuloma: caused by TB, Leprosy when you can’t clear the organism and a giant

Macrophage is surrounded by Th1. Celiac Disease:

HLA-DQ2/8 Genetic Susceptibility Gluten (gliadin) is degraded to a resistant fragment that enters gut tissue. Transglutaminase deaminates (gln glu) and T-Cell responds to the

deaminated peptide. Contact Dermatits – Second Exposure to Poison Ivy Autoimmune diseases

AUTOIMMUNITY:

Autoimmunity: a problem with self versus non-self discriminationo Caused by Failure of Tolerance.

Three Components of Autoimmune Disease:o MHC Molecules that are able to efficiently present self-antigens.o A failure to delete or inactivate self-reactive lymphocytes.o Additional environmental and/or genetic factors.

Infection: Viral (Coxsackie DM I) or Bacterial (Grp A Strep Rheumatic Fever) Susceptibility Genes: few monogenic, mostly multifactorial, demonstrated with twin

studies. Hormonal Influence: females have an increased risk Environmental Toxins: smoking modifies self-proteins Central Tolerance

Normal Mechanism: If TCR binds AIRE-Induced tissue-specific self antigens with High Affinity Apoptosis

AIRE allows deletion of auto-reactive Thymocytes AIRE influences the expression of thousands of peripheral tissue-specific

antigens in the Thymic Medullary Epithelial Cells (MEC) AIRE promotes ectopic gene expression. AIRE promotes Negative Selection of Thymocytes AIRE promotes differentiation into Tregs

Peripheral Tolerance Not all self-reactive cells ar deleted in the Thymus Prevent Peripheral autoreactive cells from causing Pathology Mature Self-Reactive T-Cells and B-Cells:

o Inactivated (Anergy)o Suppressed by Tregs (CD4+CD25+Foxp3+)

Secrete IL-10 and TGF-Bo Kept Immunologically ignorant

Loss of B-Cell Tolerance: Deletion of Self-Reactive IgM+ B-Cells in the Bone Marrow is not 100%

efficient.o Normal people have auto-reactive B-Cells.o However, normally, a parallel auto-reactive T-Cell will be absent

and/or a Treg will be present, so you are unlikely to have T-Cell help for the Auto-reactive B-Cells.

The auto-reactive B-Cells become more obvious with age. Release of Sequestered Antigen:

Unveiling of antigens not previously accessible to the Immune System. Immune Cells react to these as foreign. Privileged Sites: eyes, brain, testes, uterus Example: Eye Trauma elicits damage to the other eye.

o Leads to recognition of auto-antigens by auto-reactive T-Cells and/or B-Cells (autoantibodies)

Monogenic Diseases: The Exceptions o APECED Syndrome:

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy Syndrome Also called Autoimmune Polyendocrinopathy Syndrome (APS)

AIRE is blocked No Central Tolerance Self-Reactive T-Cells are NOT eliminated Defective generation of Tregs in Thymus

Autoimmune attack on many tissueso IPEX Syndrome:

Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome TREGS are absent or non-functional.

Multi-organ Autoimmunity Multiple clinical phenotypes, varying severity.

Treatment: Hematopoietic Stem Cell Transplantation within first year of life.o ALPS:o SLE:

Epitope Spreading: o Causes the Immune Response to spread so that different epitopes may be recognized

at different stages of the disease. Intermolecular Epitope Spreading: Response spreads to epitopes on different

antigens. Example: A single T-Cell can activate multiple B-Cells specific for different

components of a molecular complex (nucleosome) Intramolecular Epitope Spreading: Response spreads to different epitopes on the

same antigen. Mechanism is unclear.

ORGAN-SPECIFIC AUTOIMMUNE DISEASES:

AUTOIMMUNE DISEASE NAME

HSR TYPE

MUTATION PHENOTYPE TESTING ADDITIONAL INFORMATION

Autoimmune Hemolytic

Anemia

Type II Anti-RBB Autoantibodies bind to

RBCs

1. Molecular Mimicry

2. Rh Factor mismatch.

3. Drug-Induced (Penicillin)

RBC are destroyed by Phagocytosis (Opsonization or

Complement – MAC)

Occurs in Liver and Spleen.

Detect autoantibodies

using direct Coombs Test

Spherocytes are present in Blood

Smear.

Cytotoxic

Cold Agglutinins: IgM

Warm Agglutinins: IgG

Goodpasture Syndrome

Type II Anti-Type IV Collagen Autoantibodies

A3 ChainGlomerular Basement

Membrane

Phagocytes and Complement

Activation causes inflammation and tissue damage in

the kidney.

Histology shows “linear” IgG

deposition along capillary loops.

Cytotoxic

More common in men.

Pemphigus Vulgaris

Type II Anti-Desmoglein AutoantibodiesIgG1 and IgG4

Loss of Cell-Cell Adhesion

(Acantholysis)

Formation of blisters.

Immunohistological demonstration of anti-desmoglein

detection of Acantholysis.

Cytotoxic

High frequency in Ashkenazi Jews

Myasthenia Gravis

Type II Anti-AchR Autoantibodies

Blocks binding of Ach and triggers

destruction of AchR

Poor muscle contraction.

Ptosis.Weak breathing.

Anti-AchR Antibodies in

Serum

Non-Cytotoxic

Treat with Acetylcholinesterase

Inhibitor

Lambert-Eaton Syndrome

Type II Anti-Voltage-Gated Ca2+ Channel

Autoantibodies

Block release of Ach

Poor muscle contraction.

Ptosis.Weak breathing.

Anti-Voltage-Gated Ca2+ Channel

Autoantibodies in Serum

Non-Cytotoxic

Grave’s Disease Type II Anti-TSH-R Autoantibodies

Autoantibodies stimulate the receptor,

causing Hyperthyroidism.

Overproduction of T3/T4.

No Negative Feedback.

Goiter.

Exophthalmos

T3/T4 levels

More common in males.

Non-Cytotoxic

Anti-Thyroid Drugs.Thyroid Removal by

Radioiodine.Treat with

Plasmapheresis to remove

Autoantibodies.Type I Diabetes Type IV Anti- β -Cell

Autoantibodies in the Pancreatic Islets

Decarboxylase 65 (GAD65) is cross-

reactive with Coxsackie Virus Proteins.

Destruction of Insulin-Producing

Cells

Hyperglycemia

Anti-GADD45 Autoantibodies.

High Blood Glucose.

β -Cell-Specific Th1 Cells make IFNy.

Macrophage Activation.

β -Cell Specific CTL

Hashimoto’s Thyroiditis

Type IV Anti-ThyroglobulinAnti-Thyroid Peroxidase

Autoantibodies

DTH (Th1) in Thyroid

CD4/CD8 T-Cells & B-Cells infiltrate and form Ectopic Lymphoid Tissue

in Thyroid.

Thyroid Histology shows well-developed

Germinal Centers.Antibodies to TPO and Thyroglobulin

Treat with Synthetic Thyroid Hormone

Daily.

Addison’s Disease

Type IV Anti-21-Hydroxylase Autoantibodies

Destruction of the Adrenal Cortex

Deficiency of Aldosterone and

Cortisol

Auto-reactive CD8 and Th1 Cells

IFN-Y-Dependent Macrophage Activation

Pernicious Anemia

Type IVType

II?

Anti-Intrinsic FactorAnti-Parietal Cell Autoantibodies

Vitamin B-12 Deficiency

Detection of Anti-Parietal Cell and

Anti-IF Antibodies.

Evidence of Type IV response.

New Evidence of Type II

Multiple Sclerosis

Type IV Anti-Myelin Basic Protein (MBP)

Anti-Myelin Oligodendrocyte

Glycoprotein (MOG)Autoantibodies

Chronic Inflammation

Destruction of Myelin Sheath of

Nerve Fibers in the Brian and Spinal

Cord due to Auto-reactive T-Cells

Detection by areas of demyelination

(plaques or scleroses)

Neurological disability

Autoreactive Th1 Cells.

Demyelination is mediated by CNS-

Resident Macrophages (Microglial).

Th17 Cells could play a role in Pathogenesis

Inflammatory Bowel Diseases

Type IV NOD2 Gene Mutation

IL-23 Polymorphisms

Crohn’s Disease: lesions in any part

of the GI Tract

Ulcerative Colitis: Continuous

mucosal inflammation of

the rectum/colon.

Th17 = Pro-Inflammatory

Cytokine, plays role in pathogenesis.

Celiac Disease Type IV Anti-Endomysial and Anti-Tissue

Transglutaminase Antibodies

Sensitivity to a-gliadin (gluten)

HLA-DQ2HLA-DQ8

Detection of Anti-Endomysial and

Anti-Tissue Transglutaminase

Antibodies in Serum.

Stressed enterocytes secrete Zonulin, which

disrupts tight junctions, allowing a-

gliadin to pass Transglutaminase modifies a-gliadin peptides Th1

Response

SYSTEMIC AUTOIMMUNE DISEASES:

AUTOIMMUNE DISEASE NAME

HSR TYPE

MUTATION PHENOTYPE TESTING ADDITIONAL INFORMATION

Systemic Lupus Erythematous (SLE)

Type III

Complement Deficiencies

(C1Q, C2, C4)

Anti-dsDNA, Anti-SnRNP,

Anti-Sm

UV Light Trigger

Highly variable symptoms and severity, also

episodic.

Butterfly Rash

ANA (Anti-Nuclear Antibody) – not specific

for Lupus

Abs:Anti-dsDNA, Anti-SnRNP, Anti-Sm

Most common Autoimmune

Rheumatic Disease

Rheumatoid Arthritis (RA)

Type IV

Autoreactive CD4+ Th1 and

Th17 Cells against Synovial

Tissue

Th17 IL-17 Neutrophils Inflammation

Th1 TNF-a MMPs that destroy cartilage and bone.

No Diagnostic Testing

Detection of IgM Rheumatoid Factor

(IgM anti-IgG)

Seropositive RA (RF+) more aggressive

New Test: Detect Anti-CCP Autoantibodies(Cyclic Citrullinated Peptides)

Episodic, Chronic

Treatments:TNFa Inhibitors

(Infliximab, Adalimumab,

Etanercept, TNFR-Ig)

Anti-CD20 mAb (destroys B Cells using

NK Cells)

Sjogren’s Syndrome Type III

Autoimmune Destruction of

Exocrine Glands

Destroys Lacrimal and Salivary

Glands, Respiratory Mucosa, Vaginal

Secretions

Shirmer’s Test (tear production)

Spit Test

Anti-Ro, Anti-La Autoantibodies

Treatment: Fluid Replacement

Wegener’s Granulomatosis

Type III

Anti-Neutrophil Cytoplasmic Antibodies

c-ANCA

Target:Proteinase 3

(PR3)

Inflammation of Blood Vessels

Autoantibodies bind to neutrophils

and induce a Respiratory Burst

Detection of Anti-PR3 ANCA (cANCA) in Serum

Saddle Nose

Cavitary Lung Lesions

Slight more common in males.

Pulmonary Vasculitis

Ankylosing Spondylitis (AS)

Strong association with

HLA-B27(Molecular

Mimicry or Auto-antigen)

Chronic Spinal Inflammation

New bone growth and fusion of

vertebrae

- 90% Male

Ankylosis: bent

Scleroderma Type III or Type

IV

Anti-CentromereAnti-Scl-70

Anti-RoAnti-RNP

Autoantibodies

Chronic Fibrosing Disease

Highly variable symptoms:

Raynaud’s SyndromeSclerodactlylDigital Ulcers

Types:1. Limited Cutaneous: hands, arms, face, feet.2. Diffuse Cutaneous: extensive skin + internal organs

TRANSPLANTATION:

Graft Classifications:o Autogeneic/Autograft:

From Self to Self Accepted

o Syngeneic or Isograft: Graft between identical twins. Accepted

o Allograft Graft between genetically dissimilar individuals Rejected Most common

o Xenograft Graft between different species Rejected the most. Mostly pigs. Cause Hyperacute Rejections

Targets for Allograft and Xenograft Rejection:o Blood Group Antigens (ABO)o MHC I and MHC II

Direct: T-Cell recognizes donor’s MHC Presentation (donor APC) MHC I or MHC III

Indirect: Processing is done by recipient APC and recognized there. Only MHC II

o Minor Histocompatibility Antigens (Polymorphic Proteins) Graft Survival:

o 1st Match: HLA-DR (MHC II)o 2nd Match: HLA-A (MHC I)o 3rd Match: HLA-B (MHC I)

Graft Rejection:o Hyperacute:

Minutes to Hours Pre-formed Anti-Donor Antibodies + Complement

o Accelerated: 2-4 Days Reactivation of Sensitized T-Cells Memory Cells were made. Type IV

o Acute: 1 Week Primary Activation of T-Cells Type IV

o Chronic: Months to Years Antibody and Cell-Mediated Rejection Poorly Understood Type II

Bone Marrow Transplantation:

o Used to Treat: hematopoietic, immune system deficiencies, etc.o Challenges:

Space must be created by eliminating existing bone marrow Grafted tissue may mount an immune response to the host tissue

o Graft Versus Host Disease (GVHD) The transplanted cells contain mature and memory T-Cells T-Cells circulate in blood to secondary lymphoid tissues. Alloreactive cells interact

with Dendritic Cells and proliferate. Effector CD4 and CD8 T-Cells enter tissues already inflamed from the chemotherapy and radiation, and cause further tissue damage.

o Immunosuppressive Therapy: Prevent activation and proliferation of T-Cells

Cyclosporin, FK-506o IL-2 Production Inhibitors

IL-2 antagonist mAbs, Anti-CD25 Abso Rapamycin (Sirolimus)o IL-2 Signaling Inhibitors

Cytotoxic Drugso Remove actively dividing cells.o Azathioprine, Cyclophosphamide

Deplete Peripheral T-Cellso Anti-CD3 mAB, anti-CD4, anti-CD2

Inhibitors of Inflammatory Responseso Corticosteroidso Decrease IL-1, iL-6, IL-8, TNF-A, CAMs, Prostaglandins, Leukotrienes

Experimental Therapies: Belatacept: Blocks Co-Stimulation (CD28)

o CTLA4-Igo Block CD40L – Anti-CD40L Abo Inhibit Signal 2 so there is no T-Cell Activation

IMMUNODEFICIENCES:

IMMUNODEFICIENCY DISEASE NAME

MODE OF INHERITANCE

MUTATION PHENOTYPE TESTING ADDITIONAL INFORMATION

Leukocyte Adhesion Deficiency (LAD)

Autosomal Recessive

No CD-18No LFA-1

Lack of Complement

Receptors.Firm adhesion and Diapedesis of Neutrophils does not occur.

Recurrent Infections.

No pus.Elevated WBC

Count.

Rebuck Skin Window:

Skin abraded and cover

slip applied to visualize

adhered leukocytes.

Treatment: BMT

Chronic Granulomatous

Disease(CGD)

X-Linked Deficiency of NADPH OxidaseSubunit: gp91

Recurrent Infections

Nitro Blue Tetrazolium (NBT) or DHR (oxidizing capacity)

Chediak-Higashi Syndrome

(CHS)

Autosomal Recessive

Lysosomal Trafficking

Regulator GeneLYST

Giant granules in all cells containing

lysosomes, abnormal NK Cell

Activity

- -Partial Albinism

Paroxysmal Nocturnal

Hemoglobinuria

PIGA MutationLack of CD55

(DAF) and CD59C3 Convertase

is defective.

Wakes up with Blood in UrineC3 Convertase

cannot be anchored and we are not

saved from lysis.

- -DAF = Decay Accelerating

Factor

C1 Esterase Inhibitor (C1-INH) Deficiency.

Hereditary Angioedema (HAR)

Autosomal Dominant

No C3 Convertase is

formed.

Edema due to Bradykinin

Pathway

- Treatment: C1 Inhibitor

Bradykinin Antagonist:

Icatibant.Kallikrein Inhibitor:

Ecallantide

X-Linked Agammaglobulinema

(XLA)Bruton’s A

X-Linked Recessive

No AntibodiesNo MATURE B-

CellsMutation in btk

GeneBTK: Bruton’s

Tyrosine Kinase

No TonsilsNo Lymadenopathy

Get no transduction through Pre-B-Cell

Receptor

No detectable antibodies.Normal T-Cells LevelsNo/low circulating B-Cells

Maternal IgG protects the infant. Cell-

Mediated still works = no viral

infections.Bad Bacterial

InfectionsX-Linked Hyper-IgM X-Linked Defect in CD40L T-Cells are unable High/normal Fungal

Recessive (CD154) on T-Cells

to help B-Cells class switch

levels of IgMNo other classesNeutropenia

infections!

Activation Induced Cytidine Deaminase

Deficiency (AID)

Autosomal Recessive

Hyper-IgM

AID Defect T-Cells are unable to help B-Cells Class Switch.

Lack of Somatic Hypermutation.Giant Germinal

Centers Lymph Node Hyperplasia.

Only IgMGiant Germinal Centers

-

Selective IgA Deficiency

Unknown Total absence of IgA

Mucosal defences weakened

May also have IgG2 defect

Purpura: antibodies produced against platelets, platelets destroyed in spleen bruises

Asymptomatic until transfused

with blood containing

normal IgA Anaphylatic

ReactionIgE Anti-IgA

AbsCommon Variable Immunodeficiency

(CVID)

Low levels of Serum

Immunoglobulins

B-Cell Defect

ADULT LIFE (20-30)

Variable degrees, common.

Ig Levels decrease with time.

Normal T-Cell levels.

- -

Selective IgG Subclass Deficiency

Low levels for age of IgG Subclass

Normal B CellsNormal T CellsIgG2 Subclass

Deficiency

Normal levels of other Igs

Treatment: Antibiotics,

some children outgrow it.

T-CELL DEFICIENCIESDiGeorge Syndrome Abnormal

development of fetal cells and tissues of the

neck.No Thymus

No T-Cells22q11 deletion

Neonatal Hypocalcemia

Chest X-Ray shows lack of Thymic

ShadowVelocardiofacial

Syndrome

Measure the proportion of CD4 Cells

Intracellular Infections from

Birth

Bare Lymphocyte Syndrome (BLS) Type 1

MHC Class I Deficiency

Mutations in TAP1 and TAP 2

No CD8 CellsEndogenous

Pathway

- Intracellular Infections from

Birth

Bare Lymphocyte Syndrome (BLS) Type

2

MHC Class II Deficiency

Mutation in CIITA (MHC II

There is no CD4 T-Cells.

No class switching – only IgM

- Intracellular Infections from

BirthConsidered as a

transactivator) or RFX

(Regulatory Factor X)

Exogenous Pathway

SCID

SCIDADA

Autosomal Recessive

ADA DeficiencyAdenosine Deaminase

Presents in infancy.T-, B-, NK-

All Negative

Accumulation of Adenosine is toxic to Lymphocytes.

- Treatment: PEG-ADA or

Haploidentical BMT

SCIDPNP

Autosomal Recessive

PNP DeficiencyPurine

Nucleoside Phosphorylase

dGTP is toxic for T-Cells, but not B-

Cells.T-, B+, NK+

Lymphopenia

- Not as severe as ADA.

X-Linked SCID X-LinkedMost Common

Mutation in the y-chain of the IL-2 Receptor

No IL-2Ry on B-Cells

T-, B+, NK-Lymphocytopenia

Early deathVulnerable to Viral,

Fungal, Bacterial Infections

Non-random inactivation of X Chromosome in mother’s T-Cells

Omenn Syndrome: Autosomal Recessive SCID

Mutation in RAG1/RAG2

Artemis (cross-link repair)

EosinophiliaIgE Elevated

No CD19Poor PrognosisHuge Thymus

Wiskott-Aldrich Syndrome (WAS)

X-Linked Recessive

Mutation in WASP

Platelets do not function

properly and are destroyed.

Cannot form blot clots

Classic Triad:Thrombocytopenia,

Severe Eczema, Recurrent Pyogenic

Infection.

WBC and Megakaryocyte express WASP

Susceptible to encapsulated

bacterial infection.

Treatment: BMT

Ataxia Telangiectasia (AT)

Autosomal Recessive

Mutation in ATM Gene

Selective IgA Deficiency very

common.

Cerebellar Ataxia, Telangiectasia,

Recurrent Sinus Infection.

Ionizing radiation.

DNA Breaks will accumulate because you

cannot repair them.

X-Linked Lymphoproliferative

Syndrome (XLP)

X-Linked Defect in SH2D1A

SAP = SLAM Associated

Protein

Absence of effective T-Cell Control for EBV

InfectionMononucleosis

Most die by age 10, all by age

40.

B-CELL MALIGNANCY

MODE OF INHERITANCE

MUTATION PHENOTYPE TESTING ADDITIONAL INFORMATION

Multiple Myeloma - Bone destruction is mediated by MIP-1a

and RANKL

Presence of Monoclonal

IgG

Bone pain, renal failure,

and recurrent infections.

Monoclonal Paraprotein

Lytic Bone Disease

Bence Jones Proteins lead

to renal failure.

Ig production is decreased but thereare

increased levels of Igs in

the blood.

Cancer of Plasma Cells

Proliferation of Myeloma Cells depends on IL-6

Waldenstrom’s Macroglobulinemia

Presence of Monoclonal

IgM

Elderly males

No Lytic Bone Disease

Hyperviscosity

HIV/AIDS:

Steps:o Dendritic Cells bind to HIV using DC-SIGNo HIV is internalized into early endosomeso Dendritic Cells migrate to Lymph Nodes and transfer HIV to CD4 T-Cells.

Replication Cycle:o Entry of HIV into cells

GP120 binds to CD4 on T-Cells and Macrophages/Monocytes GP120 changes conformation and binds CCR5 or CXCR4 GP41 has pH independent fusion activity (neutral pH)

o Reverse Transcription Reverse Transcriptase copies Viral RNA Genomes into dsDNA

o Integration Viral cDNA enters nucleus and is integrated into host DNA

o Transcription Activated T-Cell is Permissive

o Translationo Assembly and Budding

Course of Untreated HIV Infection:o 2-6 Weeks: Drop in CD4, Flu-Like Diseaseo Mean of 10 Years: Asymptomatic Phase, Clinical Latencyo Symptomatic Phaseo AIDS: CD4 under 200

Latent Reservoir: From infection to CD4 above 200. CD4+ T-Cell Depletion:

o Infected, Activated CD4 cells die as a result of viral assembly and buddling.o Infected CD4 T-Cells can form Syncytia with uninfected CD4 T-Cellso Infected CD4 T-Cells are killed by HIV-Specific CD8 CTLo Chronic Immune Activation of CD4 T-Cells may lead to apoptosis

Could kill themselves or neighboring CD4 using Fas. Immune Response to HIV

o Window Period: 4-8 Weeks You have the virus but do not have Antibodies in the serum. Seronegative Dangerous for blood donation

o 2-12 Years: Presence of HIV Specific CD8o 2-3 Years: Rise in Viral Load with drop in CD4 T-Cells

HIV Symptomso Microglia Express CD4o Formation of Multinucleated Giant Cells in HIV-Infected Braino Infections: Opportunistic

Pneumocystis Jiroveci opportunitistc Infection Kaposi’s Sarcoma (HerpesVirus) Mycobacterium tuberculosis, avium Viruses that are usually latent become infections

Testing:o 2x ELISA + Confirmatory Western Blot

The window period was problematic with this; so subsequent generations of ELISA were done to figure out how to deal with the window period.

Most recent protocol: Nucleic Acid testing in Minipools shortens the window period. 4th Generation Elisa: They adding the other strain of HIV (HIV1&2). You look

for antibody to both. They now also look for p24 antigen. They have added an antibody to p24 to the plate, so that they can also detect antigens for HIV, not just the antibody (minimizing the window problem).

Therapy:o Goals:

Suppress the Viral Load Improve Quality of Life Prevent Transmission

o Drugs: Block Fusion:

Block CCR5 Block RT

Block Integration Block Maturation

GP160 GP120, GP41o Drug Classes:

HAART: 2NRTIs + a PI/NNRTI/II Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTI) Non-Nucleoside Reverse Transcriptase Inhibiors (NNRTI) Protease Inhibitor (PI) Integrase Inhibitor (II) CCR5 Antagonist Fusion Inhibitors Target GP41

HAART: Highly Active Anti-Retroviral Therapy

Notes By: Brittni McClellan