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USMLE First Aid

Immunology

Lymph
Node

A Secondary Lymphoid
Organ that has many
afferents and 1 or more
efferent.
Encapsulated, has
trabeculae.
Functions:
Non-specific
Filtration by
macrophages
Storage and
activation of B and
T Cells
Ab production

Post-Capillary High
Endothelial Venules

Lymph Node

Lymph Node: Follicle


Site of:
B-cell localization and
proliferation
Located in:
Outer Cortex
Primary Follicles are inactive
Dominant numericaly
Secondary Follicles
Active
Contain pale centers called:
Germinal Centers
This is the are where Bcells proliferate when
activated

Subcapsular
Sinus

Capsule

Paracortex

Germinal
Center

Cortex

Follicle

Lymph Node: Medulla


Consists of:
Medullary Cords
Closely packes
lymphocytes and
plasma cells

Medullary Sinuses
Communicate with
efferent lymphatics
Contain
Reticular cells
Lymphatics

Lymph Node: Paracortex


Houses:
T-Cells
Between:
Follicles and medulla
Contains High
Endothelial Venules
through which T and B
cells enter form blood

In an extreme cellular
immune reponse, the
paracortex becomes:
Extremely enlargedNot
well deveoped in patients
with:
Digeorges Syndrome

Lymph Node Histology Quiz


Start at top Left and go clockwise
Seondary
Follicle
Medullary
Sinus

Germinal
Center

Subcapsular
(Marginal) Sinus
Medullary
Cord
Simple Cuboidal
Epithelium

Primary
Follicle
Capsule

Lymphocytes undergoing
Diapedesis
High Endothelial Venules

Paracortex

Lymphatic Drainage
Area of Body

Primary Lymph Node Drainage Site

Upper Limb, Lateral Breast

Axillary

Stomach

Celiac
Superior Mesenteric

Duodenum, Jejunum
Sigmoid Colon
Lower Rectum, Anal canal above
pectinate line
Anal canal below pectinate line
Testes
Scrotum
Superficial Thigh
Lateral Side of Dorsal Foot
These Nodes are drained into the
Right and Left (thoracic) Lymphatic
ducts for return to systemic
circulation

Colic to inferior mesenteric


Internal Iliac
Superficial inguinal
Superficial And Deep plexuses to para-aortic

Superficial Inguinal
Superficial Inginual
Popliteal
Right Lymphatic Duct Drains
Right arm, Right Half of Head
and Chest
Left (Thoracic Duct) Drains
Everything Else

Spleen
The link below is a page which gives a full
lesson on Splenic anatomy and function.
http://education.vetmed.vt.edu/curriculum/vm
8054/labs/Lab13/Lab13.htm

Sinusoids of Spleen
Long Vascular
Channels in red pulp
with fenestrated
membrane describes
as:
Barrel-hoop

Macrophages are found


near-by.
Function?
Remove encapsulated
bacteria

T-Cells are found in


the
PALS and the Red
pulp

B-Cells are found in


the:
follicles in the white
pulp

Spleen Histology
Follicle (B-Cells)

White Pulp

Central Arteriole

PALS
(T-Cells)
Red Pulp

Division between red and white pulp

Thymus
Site of:
T Cell differentiation
and maturation
Encapsulated
From what branchial
origin?
Epithelium of 3rd
pouch

Lymphocytes are of
what origin?
mesenchymal

Cortex
Dense
Immature T-Cells

Medulla

Pale
Mature T-Cells
Reticular epithelial cells
Hassals Corpuscles

Where do positive (MHC


restriction) and negative
(non-reactive to self)
selection take place?
Corticomedullary junction

Thymus Histology

Hassals Corpuscle
Found only in:
thymic medulla
Cortex

Corticomedullary
Juction

Made from:
type VI epithelial
reticular cells

Lobule
Medulla
Capsule

Innate vs. Adaptive Immunity


Innate
Receptors that recognize
pathigens are germline
encodes
Response is fast and
non-specific
No Memory
Consists of

Neutrophils
Macrophages
Dendiritic cells
Complement

Adaptive
Receptors that recognize
pathogens undergo VDJ
recombination during
lymphocyte development.
Response is slow on first
exposure.
Memory reposne is faster
and more robust
Consistis of:
T-Cells
B-Cells
Circulating Ab

Differentiation of T-cells
Bone Marrow

Thymus

Lymph Node
CD8+ T-cell

T-cell
Precursor

Cytotoxic T-cell

CD4+ CD8+
T-cell
TH1 T-cell

Activate
mactophages
and CD8+ Tcells

IFN- IL-12
CD4+ T-cell

Helper T-cell

12
IL-

IL4

IL-4, IL-5

TCR
CD8
CD4

TH2 T-cell

IFN- inhibits TH2 Cells


IL-4 inhibits TH1 Cells

Help B-cells
make Ab
(IgE > IgG)

Th1 or Th2 Response


(Copied from my WUMS I immuno review)
THo cells are naive T cells before antigen stimulation
Stimulation leads to Th0 expression of IL2 and IL2R
IL-2 autostimulation causes proliferation and differentiation into Th1 or Th2
Th1- Bacterial infections
IL-12 produced by cells of the innate immune system binds Th0 cells and causes them to
become Th1.
Th1 produces IFNgamma which in turn stimulates the innate immune cells to express more
MHC and B7, kill intracellular pathogens, and produce even more IL12, perpetuating TH1
differentiation.
IFN gamma activates macrophages
Th2

Parasites and allergy


In the presence of IL-4 Th0 become Th2
Th2 produce IL4, IL13, IL10, and IL5
IL10 and IL13 inhibit macrophage activation
IL 4 and 5 augment mast cell and eosinophil responses
IL4 promotes class switch to IgE
IL5 activates mast cells and eosinophils

MHC I and MHC II


Encoded by HLA Genes

MHC I

HLA-A, HLA-B, HLA-C


Expressed on almost all
nucleated cells
Antigen is loaded in RER with:

Intracellular peptides
Mediates immunity to?
Viruses

Pairs with what protein:


2 Microglobulin

MHC II

HLA-DR, HLA-DP, HLA-DQ


Expressed on
APCs
Antigen is loaded in
An acidified endosome
Presents:
Extracellular peptides

Major Functions: B-cells


Make Antibody
IgG function
Opsonizes bacteria and viruses
Cytotoxic (Type II) and Immune complex
hypersenstivity

IgE Function
Allergy (Type I Hypersensitivity)

Ab can cause organ rejection


What kind?
Hyperacute

(Type III)

Major Functions: T-cells


CD4+ T-cells help
Make antibody
Recognize MHC II
Produce -interferon which:
Activates macrophages

CD8+ T-cells kill:


Virus infected cells
Recognize MHC I

Delayed-type hypersensitivity (type IV)


Allograft rejection
What type?
Acute and chronic

T-cell glycoproteins
Helper T-cells have:
CD4 which is
recogized by:
MHC II on:
APC

Cytotoxic T-cells
have:
CD8 which binds to:
MHC I on:
Virus infected cells

CD3 complex
Cluster of
polypeptides
associated with TCR.
Important in signal
transduction

APC (3 types)
Macrophages
B-Cell
Dendritic Cell

Virus Infected Cell

MHC I
Virus
IgM

CD19

Virus
Viral
Epitope
APC

TCR
B Cell

CD8+
MHC II

CD20
IL2,

Plasma Cell

IFN

Viral
Epitope

IL-4
, IL5

TCR
CD4+
TH Cell
IL-2

Antibody

CD4+ T-Cell Activation


2 Signals Are Required, Signal 1 and Signal 2
Virus

1.

Foreign body is
phagocytosed by APC
2. Foreign Antigen is presented
on MHC II and recognized
by Th cell
Signal 1
3. Costimulatory signal is given
by interaction of B7 (on
APC) and CD28 (on Th)
Signal 2
4. Th cell is activated to
produce cytokines

APC

B7

MHC II

Antigen
CD28

TCR
CD4+

IL-2

TH Cell
CD3

IL-2

To CD8+
Cells

CD8+ T-Cell Activation


2 Signals Are Required, Signal 1 and Signal 2

1. Endogenously
synthsized (Viral or
self) proteins are
presented on MHC I
and recognzed by TCR
on Tc Cell

Virus
Virus Infected
Cell
MHC I

Antigen

Signal 1

2. IL-2 from Th cell


activates Tc to kill virus
infected cell
Signal 2

TCR
CD8+

To CD8+
Cells

T Cell
CD3
IL-2
Receptor

IL-2

Active
CD4+
TH Cell
IL-2

Antibody Structure

Interchain Disulfide bond

Recognizes antigen:
Variable parts of both L and H
chains
Fixes compliment:
Fc portion of IgM and IgG
Contributes only to the Fab fraction:
Light Chains
Properties of the Fc Region:
Constant
Carboxy terminal
Compliment-fixing
IgM and IgG only
Carbohydrate side chains

Carbohydrate Side Chain

Intrachain
Disulfide bonds

Antibody Facts
Functions
Opsonization
Due to Fc Receptors
on phagocytes

Neutralization
Prevents bacterial
adherence

Complement
Activation
Complement then
opsonizes or lyses.

Ab Diversity is
generated by
Random VJ (light chain)
or VDJ (heavy chain
recombination.
Random combination of
heavy and light chains
Somatic hypermutation
Nucleotide addition
during recombination by:
Terminal
deoxynucleotidyl
transferase

B-Cell Class Switching


Mature B Cells express ____ and
_____ on their surfaces.
IgM and IgD

They may differentiate by isotype


switching mediated by cytokines and __
CD40L

This allows the creation of plasma cells


that secrete IgA, IgE, or IgG

Immunoglobulin Isotypes
IgG

IgA

Main antibody in _____


response
Secondary immune

Fixes complement
Crosses Placenta
Defense against bacteria:
opsonization

Defense against viruses


and bacterial toxins:
neutralizes

Prevents attachment of
bacteria and viruses to
mucus membranes.
Does NOT fix
complement
Monomer or Dimer
Found in Secretions
Picks up ______ from
epithelial cells before
secretion:
Secretory component

Immunoglobulin Isotypes
IgM

IgD

Produces in ____
response to antigen
Primary immune

Fixes complement
Does not cross the
placenta
Antigen receptor on
surface of B-Cells
Monomeric

Otherwise is pentameris

Unclear Function
Found on surface of
many____
B-Cells

Also found in serum

Immunoglobulin Isotypes
IgE
Mediates immetidate (type
I) hypersensitivity) by
inducing degranulation of
mast cells and basophils
upon binding to allergen
Mediates immunity to
worms by activating:
Eosinophils

Lowest Concentration in
serum
Probably because it is all
bound to mast-cells

Ig Epitopes
Allotype
Ig epitope that differs
among members of
the same species
Normal genetic
diversity

Isotype
IgA, IgG, IgM, IgD,
IgE

Idiotype
Specific for a given
antigen
Ig epitope is
determined by the
antigen binding site.

Cytokines
IL-1
Secreted by:
Macrophages

Causes:
Acute inflammation

Induces chemokine
production to recruit
leukocytes
Activates endothelium to
produce:
Adhesion molecules

Is endogenous pyrogen
Raises body temp

IL-2
Secreted by ____
Cell
Th

Stimulates growth of
_____ and _____
Th and Tc cells

Cytokines
IL-3

IL-4

Secreted by:
Activated T-cells

Supports growth and


differentiation of:
Bone marrow stem cells

Has a functions similar


to:
GM-CSF (stands for?)
Granulocytemarophage colony
stimulating factor

Secreted by TH2
Cells
Promotes growth of:
B-cells

Enhances class
switching to:
IgG and IgE

Cytokines
IL-5
Secreted by:
Th2 Cells

Promotes differentiation
of:
B-cells

Enhances class
switching to:
IgA

Stimulates production
and activation of:
eosinophils

IL-6
Secreted by:
Th cells and
Macrophages

Stimulates
production of:
Acute phase
reactants and
antibodies

Cytokines
IL-8
Secreted by:
Macrophages

Major chemotactic
factor for:
neutrophils

IL-10
Secreted by:
Regulatory T-cells
(Treg)

Inhibits actions of
activated T-Cells

Cytokines
IL-12
Secreted by:
B-Cells and
Macrophages

Cytokines
Interferon-
Secreted by:
Th1 Cells

Stimulates:
macrophages

TNF-
Secreted by:
Macrophages

Mediates
Acute phase reactants
C-reactive protein

Septic Shock

Causes
Leukocyte recruitment
Septic Shock

Cell Surface Proteins


TCR
CD4

CD3
T-helper
Cell
CD40L

CD28

Cell Surface Proteins


TCR
CD8

CD3
T-Cytotoxic
Cell

Cell Surface Proteins


MHC II
IgM
CD40
B7

B- Cell

CD21

CD19
CD20

Cell Surface Proteins


MHC II
CD14
CD40
B7

Macrophage

Fc
Receptor
C3b
receptor

Cell Surface Protein


CD16
CD56

NK Cell

MHC I
Receptor

Cell Surface Proteins


MHC I

All cells
except
mature
RBC

Complement Cascade
Classical Pathway

Classical Pathway

C1q part of C1 complex binds to Fc of AgAb complex


C1q activates C1r, which cleaves C1s.
C1s cleaves C2 and C4 to C4b2a
Releases C4a (anaphylotoxin)
C4b2a (classical C3 convertase) cleaves
C3 to C3a and C3b
C3a causes chemotaxis and
anaphylaxis
C3b either :
Binds to cell surface to act an an
Opsonin
combines with C4a2b to make
C4a2b3b (C5 convertase)
C4a2b3b cleaves C5 to C5a and C5b
C5a causes anaphylaxis (mas cell
degranulation) and neutrophilo
chemotaxis
C5b attaches to cell membrane and
assembles C5b,6,7,8,9 (MAC)
MAC causes Cell lysis

Complement Cascade
Alternative Pathway

Alternative Pathway

Random C3 cleavage (tickover) to C3a


and C3b initates alternative pathways
C3b combines with factor B to form
C3bB
Factor D then cleaves factor B to Ba
and Bb leaving C3bBb (alternative C3
convertase)
C3bBb is then stabilized by binding to
Properdin
PC3bBb can cleave C3 to form
PC3bBbC3b (alternative C5
convertase)

OR C3bBb can cleave lots of C3


resulting in C3b fixation causing
opsonization.

Alternative C5 convertase cleaves C5


to C5a (anaphylotoxin) and C5b which
assembles the MAC

Complement Cascade
Lectin Pathway

Lectin Pathway
Mannan binding lectin
binds carbohydrates on
the bacterial cell
surface
This complex can
cleave C4 and C2 to
C4a2b
This pathway then
follows exactly the
same path at the
classical pathway

Complement Cascade
Visit the website below
for excellent narrative
and video depictions of
the classical and
alternative complement
pathways. They are
much better than my
shoddy descriptions.
http://www.brown.edu/Course
s/Bio_160/Projects1999/ies/h
ow.html

Complement
Membrane Attack
complex involved in
defense against:
Gram Neg. Bacteria

Classic pathways
activated by:
IgM and IgG

Alternative pathway
activated by:
Surface molecules
especially:
exotoxin

Two major opsonins


ins bacterial defense:
C3b
IgG

Regulators which help


prevent Complement
activation on self cells
DAF (decay
accelerating factor)
C1 esterase

Important Complement
Components
C1, C2, C3, C4
Viral Neutralization

C3b
Opsonization

C3a, C5a
Anaphylaxis

C5b, C6, C7, C8, C9


Membrane attack complex (cytolysis)

Complement Component
Deficiencies
C1 Esterase Deficiency
Hereditary Angioedema
C2 and C4 are depleted because C1 is too active in cleaving
them to C4b2a

C3 deficiency
Recurrent pyogenic sinus and respiratory tract infections

C6-C8 Deficiency
Nesseria Bacteremia

DAF deficiency
Complement Mediated lysis of RBCs
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Pathophys. has to do with the loss of a GPI anchor

Interferon Mechanism

Interferons (,,) are proteins


that place uninfected cells in an
antiviral state.
IFN- and IFN- do what?
Induce a ribonuclease that
inhibits viral protein
synthesis by:
Degrading viral mRNA
(but not host mRNA)

Pyrogenesis by causing
PGE2 release
Analgesia

IFN- does what?


Increases MHC I and II
and antigen presentation
in all cells
Promotes NK cells to kill
virus infected cells
Suppresses TH2 activity
Promotes adhesion
molecules for leukocyte
binding

Passive vs. Active immunity


Active
Long after exposure
Slow onset
Memory

Passive (therapy)
Based upon giving
preformed antibody from
another host after
exposure.
Half life of passive Ab = 3
weeks
Passive Therapy given
for

Tetanus Toxin
Botulinum Toxin
HBV
Rabies

Antigen Variation

Mechanisms Of
Variation
DNA rearrangement
RNA segment
reassortment
E.g. Influenza major
anigenic shift

Classic Examples:
Bacteria
Samonella:
2 flagellar variants
Borrelia
Relapsing fever
Antigenic variation allows
relapses of febrile episodes
N. Gonorrheae
Pilus protein
Viruses
Influenza
Major- shift
Minor- drift
Parasites
Trypanosomes
Programmed rearrangement

Anergy
Self reactive T-cells
become nonreactive without
costimulatory
molecule

B-Cells also become


tolerant, but
tolerance is less
complete than in Tcells.

Hypersensitivity
Type I: Immediate

Free antigen
crosslinks
preformed IgE on
mast cells and
basophils
Triggers release of
vasoactive amines
Histamine

Which two other


types of
hypersensitivity are
also antibody
mediated?
II and III

Reactions Caused by Type I


Anaphylaxis
Allergic Rhinitis (Hay Fever)

Hypersensitivity
Type II: Antibody Mediated

Preformed IgG and IgM bind to antigen


on invading cell.
Causes:
complement fixation
leading to MAC mediated cell lysis

phagocytosis.

Reactions Caused by Type II

Hemolytic anemia
Idiopathic thrombocytopenia purpura
Anti-platelet Ab

Erythroblastosis Fetalis
Rh- mother giver bith to second Rh+ baby
Rheumatic Fever
Often occurs post GAS infection
Goodpastures Syndrome
Ab to antigen in kidney and lung basement membrane
Bullous Pemphigoid
Ab to type XVII collagen in hemidesmosomes
Graves Disease
Anti-TSH receptor Ab. Causes Hyperthyroidism
Myasthenia Gravis
Anti ACh receptor Ab

Hypersensitivity
Type III: Immune Complex

Ag-Ab complexes activate complement


This attracts neutrophils
Neutrophils release lysosmal enzymes

Complications of
Type III Hypersensitivity
Serum Sickness
Ab is produced
Takes 5 days

Immune complexes are


formed and are
deposited in membranes
Immune complex
consists of?
Ab
Ag
Complement

Here they fix complement


causing tissue damage
Which of these two reactions is more common?:

Arthus Reaction
Intradermal injection of
antigen induces
antibodies which form
Ag-Ab complexes in the
skin
Causes
Edema
Necrosis
Complement activation

Serum Sickness

Reactions Caused by Type III


SLE
Rheumatoid Arthritis
Polyarteritis Nodosum
Caused by vasculitis of medium sized arteries due to antibodies
against HBV

Post-streptococcal golmerulonephritis
Immune complexes become lodges in the glomerulus

Serum Sickness
Arthus Reaction
Hypersensitivity Pneumonitis
Inflammation of alveoli due to hypersensitivity to inhaled dust
Many types

Hypersensitivity
Type IV: DTH

Sensitized T
lymphocytes
encounter antigen
and release
lymphokines which
cause macrophage
activation
Only type which is
cell mediated

4Ts of DTH

T lymphocytes
Transplant rejections
TB Skin tests
Touching
Contact Dermatitis

Diseases caused by Type IV

Type I DM
MS
Gullian-Barre
Hashimotos thyroiditis
Anti-thyroid Ab destroys the gland

GVHD
PPD test for TB
Contact Dermatitis

ACID Pneumonic for


Hypersensitivity types

Anaphylactic and Atopic (I)


Cytotoxic (II)
Immune complex (III)
Delayed type (IV)

Immune Deficiencies

Decreased production of:


B-Cells
Brutons Agammaglobulinemia
T-Cells
DiGeorge Syndrome
B and T Cells
SCID

Decreased Activation of:


T Cells
IL-12 Receptor Deficiency
B-Cells
Hyper IgM syndrome
B-Cell
Wiskott-Aldrich Syndrome
Macrophages
Jobs Syndrome

Phagocytic Cell Dysfunction


Defective LFA-1 integrin
LAD-1
Microtubular fucntion and lysosomal
emptying
Chediak-Higashi
Lack of NADPH oxidase
Chronic Granulomatous Disease

Idiopathic Dysfunction
T-Cells
Chronic Mucocutaneous candidiasis
B-Cells
Selective immunoglobulin Deficiency
B-Cell
Ataxia-Telangectasia
B-Cells
Common Variable Immuodeficiency

Brutons Agammaglobulinemia
Caused by:
Decreased produciton
of B Cells
Mutant tyrosine kinase
(Btk) which causes BCells to fail to mature
past pre-B stage

Causes:
Recurrent bacterial
infections
After 6 months of age
when maternal IgG
declines

Only affects:
Inheritance:
XLR

boys

DiGeorge Syndrome
Thymic Aplasia
Caused by:
T- Cell deficiency
Thymus and parathyroids
fail to develop due to
failure of 3rd and 4th
pharyngeal pouches

Inheritance
Autosomal DOMINANT
22q11 deletion

Presents with:
Tetany due to:
Hypocalcemia
secondary to
hypoparathyroidism

Causes:
Recurrent infections with:
viral and fungal

Congential defects of
heart and great vessels

SCID
Caused by:
Failure to present on
MHC II
Defective IL-2
Receptors
ADA deficiency
Adeoside toxicity to
lymphoid cells

Presents with:
Viral, bacterial,
fungal, and protozoal
infections

IL-12 receptor deficiency


Caused by:
Deficiency of IL-12
receptor

Presents with:
Disseminated
mycobacterial
infections with low
TH1 response

Hyper-IgM Syndrome
Caused by:
Defect in CD40 ligand on
CD4+ Th cells causes:
Inability to class switch

Decreased activity of B Cells

Inheritance
XLR
Males only
There are Autosomal forms
(CD40, UNG, AICDA
mutation) too, but VERY
rare.

Presents:
Early in life with sever
pyogenic infections

Causes:
High IgM levels
Low IgG, IgA, IgE
Large B-cell follicle
because they can still be
activated, just not class
switched.

Wiskott-Aldrich Syndrome
Caused by:
Deficiency in ability
to mount an IgM
response to capsular
polysaccharides of
bacteria

Presents with (triad):


Recurrent Pyogenic
infection
Thrombocytopenic purpura
Bloody diarrhea

Eczema

Causes:
Elevated Ig_:

Inheritance
XLR
Boys only

Normal Ig_:
E

Low Ig_:
M

Jobs Syndrome
(Hyper IgE syndrome)

Caused by:
Failure of IFN-
production by Th
cells
Neutrophils fail to
respond to
chemotactic stimuli

Presents with:
Coarse Facies
Cold (non-inflammed)
staphylococcal
abscesses
Retained primary teeth.
Increased Ig_:
E

Dermatologic problems
Eczema

Leukocyte Adhesion Deficiency Type 1


Caused by:

Presents:
Early with:

Defect in ____
protein:

Recurrent bacterial
infections
Absent pus formation
Delayed seperation of
the umbilicus

LFA-1 which is a type


of:
Integrin on:
Phagocytes

LAD-2 is associated with:


Less ___
infection
More ____
Developmental delay

Chediak- Higashi Syndrome


Caused by:
Defect in
microtubular function
and lysosomal
emptying of
phagocytic cells.

Inheritance
AR

Presents with:
Recurrent pyogenic
infections by:
Staphylococci
Streptococci

Partial Albinism
Peripheral
neuropathy

Chronic Granulomatous Disease


Caused by:
Defect in
phaygocytosis of
neutrophils owing to:
Lack of NADPH
oxidase activity

Diagnosis confirmed
by:
Negative nitroblue
tetrazolium dye
reduction test

Presents with:
Succeptibility to
opportunistic
bacterial infections
espcially:
S. aureus
E. Coli
Aspergillus

Chronic Mucocutaneous
Candidiasis
Caused by:
Idiopathic
T-Cell dysfunction
especially against
Candida Albicans

Presents with:
Skin and mucous
membrane candida
infections.

Selective Immunoglobulin
Deficiency
Caused by:
Defect in DNA repair
enzymes which
affects class
switching.
A single Ig_ isotype
is missing.

Presents with:
Sinus and Lung
infections
Milk allergies (common)
Diarrhea (common)

Causes
Deficiency in Ig_ is
most common:
A

Ataxia-Telangiectasia
Caused by:
Defect in DNA repair
enzymes.
Associated with
deficiency of Ig_:
A

Presents with:
Cerebellar ataxia
Spider angiomas
(telangiectasia)

Common Variable
Immunodeficiency
Caused by:
Defect in B-Cell
maturation
This is a diverse set
of many diseases

Can be aquired in
20s- or 30s

Causes
Circualting B-cell
levels are:
Normal

Plasma Cell Levels


are:
Decreased

Ig levels are:
Decreased

Autoantibodies
Autoantibody- Antinuclear Antibodies
Disease- SLE

Autoantibodies
Anti-dsDNA, anti-Smith
Specific for SLE

Autoantibodies
Antihistone
Drug-induced lupus

Autoantibodies
Anti-IgG (rheumatoid factor)
Rheumatoid Arthritis

Autoantibodies
Anticentromere
Scleroderma (CREST)

Autoantibodies
Anti- Scl-70
Scleroderma (diffuse)

Autoantibodies
Antimitochondrial
Primary biliary sclerosis

Autoantibodies
Antigliadin
Celiac Disease

Autoantibodies
Anti-basement membrane
Goodpastures Syndrome

Autoantibodies
Anti-epithelial cell
Pemphigus Vulgaris

Autoantibodies
Antimicrosomal, Antithyroglobulin
Hashimotos Disease

Autoantibodies
Anti-Jo-1
Polymyositis, dermatomyositis

Autoantibodies
Anti-SS-A (Anti Ro)
Sjorgens Syndrome
SS Stands for Sjorgens Syndrome

Autoantibodies
Anti SS-B (Anti-La)
Sjorgens Syndrome

Autoantibodies
Anti U1 RNP (ribonucleprotein)
Mixed connective tissue disease

Autoantibodies
Anti- smooth muscle
Autoimmune hepatitis

Autoantibodies
Anti- glutamate decarboxylase
Type I DM

Autoantibodies
c-ANCA
Wegners Granulomatosis

Autoantibodies
p-ANCA
Other Vasculitidies

HLA Subtype Susceptibilities


HLA-B27 (PAIR)
Psoriasis
Ankylosing Spondylitis
Inflammatory Bowel Disease
Reiters Syndrome (Reactive Arthritis)
Post-infectious (usually Chalmydia)
Urethritis
Conjunctivitis
Inflammatory arthritis of large joints

HLA Subtype Susceptibilities


HLA-B8
Graves Disease
Celiac Disease

HLA Subtype Susceptibilities


HLA-DR2
MS
Hay Fever
SLE
Goodpastures

HLA Subtype Susceptibilities


HLA-DR3
DM type I

HLA Subtype Susceptibilities


HLA-DR4
Rheumatoid Arthritis
DM type I

HLA Subtype Susceptibilities


HLA-DR5
Pernicious Anemia
B12 Deficiency

Hashimotos Thyroiditis

HLA Subtype Susceptibilities


HLA- DR7
Steroid-reponsive Nephrotic syndrome

Grafts
Autograft
From Self

Syngenic
From idenitical twin or clone

Allograft Graft
From non-identical individual of same species

Xenograft
From different species

Cyclosporine
Mechanism
Binds to cyclophilins
Blocks differentiation and
activation of T-cells by
inhibiting:
Calcineurin, a
phosphorylase which
norrmaly:
dephosphorylates NFAT
so that it can go to the
nucleus and start IL-2
transcription

Prevents the production of:


IL-2 and IL-2 Receptor

Cinical use:
Supresses organ
rejection
Selected autoimmune
disorders.

Toxicity
Predisposes to:
Viral infections
Lymphoma

Nephrotoxic
Preventable with:
Mannitol Diuresis

Tacrolimus (FK506)
Mechanism
Similar to
Cyclosporine
Binds to FK-binding
protein
Inhibits secretion of:
IL-12 and other
cytokines

Clinical Use

Potent
immunosuppressive
used in organ recipients
Toxicity
Nephrotoxicity
Peripheral Neuropathy
Hypertension
Pleural effusion
Hyperglycemia

Azathioprine
Mechanism
Antimetabolite
precursor of 6mercaptopurine that
interferes with:
The synthesis of
nucleic acids
Toxic to:
Proliferating
lymphocytes

Clinical Use
Kidney Transplantation
Autoimmune Disorders
Glomerulonephritis
Hemolytic anemia

Toxicity
Bone marrow supression
Active metabolite
Mercaptopurine is
metabolized byxanthine
oxidase.
Thus toxicity is exacerbated
by:
allopurinol

Muronomab-CD3 (OKT3)
Mechanism:
mAb that binds to
CD3 epsilon chain.
On the surface of Tcells.
Blocks cellular
interaction with CD3
proteins responsible
for T-cell signal
transduction

Clinical Use:
Immunosupression after
kidney transplantation

Toxicity:
Cytokine release
syndrome
Activation instead of
inhibition of T-cells
resulting in cytokine
storm

Hypersensitivity reaction

Sirolimus (Rapamycin)
Mechanism:
Binds to mTOR.
Inhibits:
T-cell proliferation in
response to IL-2

Clinical Use:
Immunosuppression after
kidney suppression in
combination with:
Cyclosporine and
corticosteroids

Toxicity:
Hyperlipidemia
Thrombocytopenia
Leukopenia

Mycophenolate Mofetil
Mechanism
Inhibits de novo
guanine synthesis
and blocks
lymphocyte
production

Daclizumab
mAb with high
affinity for:
IL-2 receptor on
activated T-cells

Recombinant Cytokines and


Clinical Uses
Drug:
Aldesleukin

Cytokine:
IL-2

Clinical Use:
Renal Cell Carcinoma
Metastatic Melanoma

Recombinant Cytokines and


Clinical Uses
Drug:
Erythropoietin

Cytokine:
epoetin

Clinical Use:
Anemias
Especially in:
Renal failure

Recombinant Cytokines and


Clinical Uses
Drug:
Filgrastim

Cytokine:
Granulocyte colony-stimulating factor

Clinical Use:
Recovery of bone marrow

Recombinant Cytokines and


Clinical Uses
Drug:
Sargramostim

Cytokine:
GM-CSF

Clinical Use:
Recovery of Bone Marrow

Recombinant Cytokines and


Clinical Uses
Cytokine/Drug:
-interferon

Clinical Use:
Hepatitis B and C
Kaposis Sarcoma
Leukemias
Malignant Melanoma

Recombinant Cytokines and


Clinical Uses
Cytokine/Drug:
-interferon

Clinical Use:
Multiple Sclerosis

Recombinant Cytokines and


Clinical Uses
Cytokine/Drug:
-interferon

Clinical Use:
Chronic Granulomatous Disease

Recombinant Cytokines and


Clinical Uses
Drug:
Oprelvekin

Cytokine:
Interleukin-11

Clinical Use:
Thrombocytopenia

Recombinant Cytokines and


Clinical Uses
Drug:
Oprelvekin

Cytokine:
Interleukin-11

Clinical Use:
Thrombocytopenia

Recombinant Cytokines and


Clinical Uses
Cytokine/Drug:
Thrombopoietin

Clinical Use:
Thrombocytopenia

Transplant Rejection
Hyperacute

Ab mediated due to the presence of


anti-donor Ab in the recipient
Occurs within what timescale?
Minutes

Transplant Rejection
Acute

Cell mediated due to:


Cytotoxic T-lymphocytes reacting against:
Foreign MHC

Rversible with immunosupressants


such as:
OKT3 and Cyclosporine

Occurs on what timescale?


Weeks after transplant

Transplant Rejection
Chronic

Ab-mediated vascular damage


Fibrinoid necrosis

Timescale:
Months to years after transplant
Irreversible

Transplant Rejection
GVHD
Grafted immunocompetent T-cells proliferate
in irradiated immunocompromised host and
reject cells with forgein proteins.
Results in severe organ dysfunctions.
Major symptoms:

Maculopapular rash
Jaundice
Hepatosplenomegaly
Diarrhea