Disease of the immune system

Chapter session 1
introduction
 To be immune is to be protected

 The term immune began to be used to

describe resistance to contagious dx that is
conferred by vaccination or previous
infection

 Immune is the special fct of lymphocytes and

macrophages that defend the body against
foreign threats but its not the only defense
Non immune defense mechanisms
 Non immune systems are important in
defending the body against microbes and
other enviromental threats

 The 1st line of defense is physical barriers

which has special features:
Non immune defense mechanisms
1- Skin:
 microbe does not grow can only populate
cz the epidermis is dry, dense, acidic PH
and has indigestable keratin

 If skin integrity lost, microbes penetrate

to area moist mainly HIV, syphlis like
moist
 Non immune defense mechanisms
2- sclera: white of eye washed by tears (Abx
quality ) and cleans every seconds by blinks

3- respiratory tract:
- With each respiration we inhale few microorg.
interferance That trap in nasal and bronchial mucous
with this
mechanisms - If reach bronchi, they are swept up to throat
promote
respitarory
by bronchial cilia
infection - If they reach alveoli alveolar macrophage
ingest them
 Non immune defense mechanisms
4-GIT: the intestine is defended by multiple
mechanisms including:
- Protective layer of mucous
- Gastric acid
- Pancreatic enzymes
- Bile salts

 GI epithelial cells are shed daily making difficult

for organisms to grip
 The normal flora : alteration allow pathogens
to establish dx
Non immune defense mechanisms
5-Genitourinary tract:
- Urine is normally sterile cz its acidic and
flushed by system avoiding retrograde

- If urinary obstruction allow bacterial

growth that extend upward
Non immune defense mechanisms
 In addition to the physical barriers, body
fluids are flushed regularly through
various filtering process
 Can capture and dispose infective agents
ex: bld , Ln, Lymph fluid

 So in addition to physical barriers there

are several innate ( non immune) cellular
and molecular defense mechanisms:
 Non immune defense mechanisms
1- phagocytosis:
 through the engulfing fct , macrophage ingest,
digest. Dispose bacteria, virus, other foreign
materials

 macrophage inhabit every organ:

- Kupffer cell in the liver
- Alveolar macrophage in the lungs
- Monocyte and granulocyte in bld and B,M,
- Microglia in brain
- Dense macrophage accumulation in spleen, Ln
Non immune defense mechanisms
2- natural killers cells:
 Named cz of innate ability to kill cancer
cells or infected cells
 Presence: L.n. , spleen, other lymphoid
tissue

3- lysosomes;
 The digestive enz of some cells ( mainly
granulocytes as PMNs)
 Non immune defense mechanisms
4- complement system:
 20 prt generates a mb attack complex that :
- digest cell mb of microbes
- stimulate wbc activity
- ensure delivery of other body defense
mechanisms
- increase vascular permeability at site of
infection
The normal immune system
 Differ from innate defense in:
- The immune system is programmable to
defend against target ( not in innate)

- The immune system is programmable,

molecularly specific defense against non
self molecules ( virus, bacteria,,)
The normal immune system
 The principle cells of immune system are
lymphocytes (present in lymphoid organs) as
L.n., spleen, BM

 The immune system is adaptable, evolving

daily as it comes into contact with foreign
molecules

 There are 2 types of immune lymphocytes :

- B cells ( secrets antibodies)
- T cells ( attacks foreign directly)
The normal immune system
 Because all our cell are constructed from
proteins ; only non self protein (foreign) stimulate
immune response

 In addition, to non self protein, some harmless,

small non prt can stimulate an immune reaction
by combining with self prt in a way that
combination become non self ‘’this molecules
called haptens’’

 Immune reaction demonstrate their effect by

production of cytokines
Programming the immune system
 The immune system is composed of 2 types
of cells
- lymphocytes: 2 types B and T
- macrophages

 Some antigens incite T cell immunity others

B cell immunity

 When stimulated by non self antigen B cells

release programmed attack prt; antibodies
into circulation
Programming the immune system
 Antigenic stimulated B lymphocyte are
microscopic distinctive and called plasma cells

 Antigenic stimulation of T lymphocyte causes

programming and release of attack cell (cytotoxic
T cell)

 B cell antibody and cytotoxic T cell are anti

antigen which attack the prt of non self microbes,
cell, pollens and kill them directly or incite an
inflammatory reaction to neutralize and eliminate
them
Programming the immune system
 In the fetus, B cell developed by bone
marrow and T cells by the thymus

 In embryogenic stage, many B cell and T

cell are capable of reacting with self but
after passing through the bone marrow
and thymus this capability is eliminated

 This mean immune system is formed of

cells capable of reacting with self except
Programming the immune system
 Except few B and T cells are capable of
reacting with self remain alive but held in
check by immune system ( no clear
reason)

 Its sometimes an immune bombs that can

attack self antigen; autoimmune dx
Programming the immune system
 Macrophages have important role in
immune system( digest, prepare, present
foreign antigen to T cells )

 Protein on surface of macrophage called

HLA ie human lymphocytic antigen or
MHC antigen ie major histocomptability
complex
B lymphocytes: humoral immune
system
 B cell react with circulating antigen and
secretes antibodies into the circulation
where they combined with antigen
‘’ humoral immunity’’

 B cell fct is dependent on T cell system

 Certain T cell help or supress B cell

activity
B lymphocytes: humoral immune
system
 B cells are processed and programmed in
fetal bone marrow then spread to other
lymphoid organs

 Represent 10-20% of circulating

lymphocytes and found in L.n.. Bone
marrow, tonsils, spleen, lymphoid patch of
GIT and bronchial mucosa ( called peyer
patches or MALT)
B lymphocytes: humoral immune
system
 Bronchial and intestinal mucus contain
high concentration of certain type of
antibody called ‘’ mucosal immune paint’’;
it protect the GI and bronchial mucosa
(that are exposed to high amount of
microbes)

 Antibodies are prime defense against

bacterial infection
B lymphocytes: humoral immune
system
 Not all cells produce antibodies, some
produce ‘’memory B cell’’ which line in
the body and react rapidly next time to
activate
Antibodies ( immunoglobulin)
 Ab formed from prt called Ig ; made of
lymphocytes and represent 20% of bld prt

 Each Ig is composed of 2 heavy chain

molecules and 2 light chain molecules

 The are 5 types of Ig ( different stx and fct) :

G, M , A, D, E ( named according to heavy
chain)
 Ig are part of the gamma globulin fraction of
bld prt
Antibodies ( immunoglobulin)
 Most immunity arises from endogenous
production of antibodies by person own
immune system

 Antibodies can transfer passively through

antibody injection ( gamma globulin)
passive immunity, it’s a temporary immunity

 Passive immunity can be gained also by

transfer of Ab from mother to fetus across
the placenta and breast milk
Antibodies ( immunoglobulin)
 The immune system produce each type of Ig
for a purpose

1- IgM antibodies :
- after antigen challenge and it’s the immediate
response of immune system to provide
quick, short term protection
- they have short life span
- called macroglobulin ( large, heavy type of ig)
- replaced after few wks or months by IgG
antibodies
Antibodies ( immunoglobulin)
 IgA antibodies:
- Heavily concentrated in breast milk,
respiratory tract and GIT mucous
- Protect those system from foreign agents

 IgD and IgE antibodies:

- Do not circulate in bld but are confined to
tissues and inflammatory cells
- IgD helps B cells in immune role
- IgE is an important tissue reactions to
pollens and allergies
Antibodies ( immunoglobulin)
 Antibodies achieve their effect by attaching
to the target foreign antigen, which is often
part of a tissue or microbial cell mb

 They achieve effect by:

- Block the fct of antigen
- Rupture cell mb to cause cell death
- Incite an inflammatory reaction to neutralize
or digest the cell or microbe
- Make cell or microbe more susceptible to
phagocytosis
Antibodies ( immunoglobulin)
 Antibody attach to freely circulating
antigen and for Antigen-antibody complex
( immune complex)

 These complex lodge in tissue and injure

them by inciting inflammatory reaction

 Antibodies can be detected by lab test

T lymphocytes : cellular immune
system
 Cellular immunity is called so bcz when
stimulated by non self antigen, T cells are
programmed and released into circulation
to attack antigen directly ( no antibodies
released)

 T cells are blind to free antigen; only react

to antigen presented to them by
macrophage or related cells; called ‘’
delayed immunity’’
T lymphocytes : cellular immune
system
 T cells have 2 main roles in immunity ;
1- programmed to recognise and attack non self
antigen (called cytotoxic cells or killer T cells),
they attack to antigen using a receptor on their
cell mb ( TCR)

2- certain T cells modulate B cells in role and

produce antibodies facilitating B cell activity ‘’
helper T cell ‘’or restrain it called ‘’suppressor T
cells’’

3- Tcell immune reaction also produces ‘’ memory T

cells’’ preprogrammed and linger in the body to
produce a rapid and long lasting immune
response the next time antigen appear
T lymphocytes : cellular immune
system
 T cells processed in fetal thymus and
represent 80% of circulating lymphocytes

 Also found in cortex of L.n. and in special

lymphoid follicles as spleen

 T cells defined against virus and fungi and

are prime mediator in immune rejection
of tissue transplants( B cell against
Bacteria)
 T lymphocytes : cellular immune
system
 T cells are indentified according to type of
prt on their receptors TCR

 TCR is composed of cluster differentiation

prt called CD antigen ie self antigen which
are used to classify types of cells according to
role in immune process
Immunity in bld transfusion
 RBC major bld groups A, B , O are
determined by specific genes: a set that
codes for the A and B bld group prt on red
cells

 However the genes are null; they do not

code for a prt ( the null state is called O)

 Children recieive one A or B gene for each

parent, so the genetic combinations are AA,
AB, AO, BO, BB, OO
Immunity in bld transfusion
 Bld grps have naturally occuring plasma
agglutinins( naturally occuring antibodies)
capable of clumbing RBC

 Type A bld contain anti B plasma

agglutinin capable of clumping clinical type
B bld

 Universal donor and universal receiver

Immunity in bld transfusion
 In addition to type A,B,O, every person RBC
have Rh type named rhesus monkeys

 Multiple Rh genes and antigens exist but only

Rh D have antigenic strength to be of clinical
importance

 Pt with RhD gene have RhD antigen or their

RBC are said to be Rh positive ( represent
85%) but pt without RhD are Rh negative
Immunity in bld transfusion
 One of the most important consequence of Rh
difference is that Rh negative mothers may
develop anti Rh antibodies if they become
sensitizied by carrying and Rh positive fetus ‘’
erythroblastosis fetalis’’

 Hundreds of minor bld grps classified according

to weal antigens on RBC cell mb : lewis, kell, duffy

 they do not figure in calculation transfusion unless

antibodies against them are present in plasma of a
pt who needs transfusion
Classification of immune disease
1- hypersensitivity disease:
- exaggerated immune reaction to certain antigens or
other molecules
- Most hypersensitivity diseases are autoimmune
disease and allergy

2- miscellaneous immune conditions: transfusion and

tissue transplant reactions

3- immunodeficiency dx: HIV

4- malignancies of immune cells: leukemia

Mechanisms of immune reaction
1- B cell reactions:
- type1: immediate hypersensitivity
- Type2: cytotoxic hypersensitivity
- Type 3: immune complex hypersensitivity

11- T cell reaction

- Type 4: cellular ( delayed) hypersensitivity
Hypersensitivity disease
 Many dx are result of hypersensitivity
reaction, the two most important types are:

- allergy: its an exagerated immune sensitivity

to certain enviromental componds ex plants;
most allergies are type1 immune reaction

- Autoimmune dx:immune reaction to body

own self tissues
 Allergic disease
 Its exaggerated immune reactivity
(hypersensitivity) to certain environmental
substances (allergens) that have little effect on
most people

 Occur by exposure to allergens (sensitizing dose);

the subsequent exposure causes the
hypersensitivity reaction

 Most allergic reactions are mediated by type 1

(anaphylaxis) immune mechanism
Allergic disease
 Allergy vs. autoimmune dx: in allergy the
reaction is exagerated but normal
immune response against foreign antigen,
whereas in autoimmune dx the immune
system attacks self antigens

 Atopy: hereditary predisposition toward

developing certain hypersensitivity
reactions as asthma
Acute systemic anaphylaxis
 Explosive generalized type 1 immune
reaction that cause fatal vascular collapse
from systemic vasodilatation or
bronchospasm and sometimes occurs
when the offending allergin finds its way
into general circulation

 Most common cause: IV drug, bld

transfusion, insect bite
Autoimmune disease
 The immune system exist to defend from
non self agents
 In autoimmune dx its our own tissues
that become the enemy; its called collagen
vascular diseases or connective tissue
diseases bcz the bld vessels and
connective tissues are the immune target
Loss of self tolerance
 Tolerance of self refers to normal lack of immune
responsiveness to ones own tissue antigens
 Normal bodies do not develop antibodies to their
own tissue

 This can be lost by 3 ways:

- Molecular mimicry: antigen from some infectious

agents share common antigenic features with self

- Antigen that has always been hidden from contact

with immune cells may become unmasked and
attacked bcz they were never inially designated as
self in the embryo
Loss of self tolerance
 This can be lost by 3 ways:
- Molecular mimicry: antigen from some infectious
agents share common antigenic features with self

- Antigen that has always been hidden from contact

with immune cells may become unmasked and
attacked bcz they were never inially designated as
self in the embryo

- Third, helper T cell or suppressor T cell activity

may become abnormal
Genetic and microbial factor in
autoimmunity
 Genetic makeup influence the tendency
to develop autoimmune dx
 Some autoimmune dx occurs in clusters
of people in family groups and several
autoimmune diseases is associated with
inheritance of HLA antigens

 Some autoimmune dx are induced by

microbes
SLE
 Multisystem autoimmune dx
 caused by type3 immune complex
hypersensitivity reaction
 Have many manifestations that can affect
organ or tissues

 SLE is characterized by multitude of

antibodies to various organs and tissue
component; its associated with ANA
antibodies
SLE
 Common dx, affect 15-30 yrs of age

 Cause: dt loss of suppressor T cells activity that

keeps in check the antiself lymphocyte immune ‘’
time bombs’’ that remain from embryologic
development of the immune system

 ANA lab hallmark: sensitive not specific +

antibodies to rbc, lympho, plt

 Pathogenesis: genetic influence

SLE clinical and pathological features
SLE clinical and pathological features
 The dx is obvious according to the
findings

 The clinical course is variable ; some pt

have minimal pb, others are seriously
affected

 30% die in 10 yrs after dx dt renal,

infection, CNS involvement
Rheumatoid arthritis and related
diseases
 Its an autoimmune dx affecting the tissue
synovium that lines joints

 Begins slowly: low grade fever, malaise,

morning joint pain, stiffness , vertebrae

 Joint: wrist, elbow, shoulder, ankle, hand jt

( interphalengeal, metacarpophalengeal)
Rheumatoid arthritis and related
diseases
 2 clinical conditions unique to RA are
helpful in clinical dx
- radial deviation of metacarpals with
ulnar deviation of fingers producing Z
deformity of the hand

- rheumatoid nodules; painless 1-2 cm sc

granulomatous nodules, not found in
other forms of arthritis
Rheumatoid arthritis and related
diseases
 Dx develop a disabling arthritis over a
decade or 2
 Diagnosis: lab test RF
Juvenile rheumatoid arthritis
 Distinct form of RA that occurs in children ;
its more serious debilitating dx than adult
RA
 They are seronegative ; lack RF in bld
 RA involve large joints: knee, elbow, ankle
 Associated with HLA- B27 genotype
 20% onset of jeuvenile RA is explosive;
condition called ‘’still dx’’
 Still dx: HGF, arthritis, large spleen, L.n.,
pleuritis, pericarditis, skin rash, inc WBC
 Spondyloarthropathies
 Group of disorders distinct from RA in the following
ways:

- Vertebral and sacroiliac jt are mainly involved; other

jts are less involved or free of disease
- Inflammation is present in jts and involve ligaments
where they attach bone
- Most pt carry HLA-B27 genotype
- RF is not present in bld( seronegative)

 A severe form; ankylosing spondilitis: IBD, psoriasis,

arthropathy, GIT infection
 Other autoimmune dx
 Sjogren syndrome:
- autoimmune inflammatory disease of lacrimal
and salivary glands
- features dry eye and dry mouth
- Affects women over 40 and associated with
other autoimmune dx as RA, SLE
Other autoimmune dx
 Systemic sclerosis: called scledorma
- Severe dx featuring inflammation and
fibrosis of interstium (fibrous intracellular
tissue) of many organs especially the
dermis
- Fibrosis: the hallmark, may affect GIT,
lungs, kidney, heart, skeletal muscle

 Manifestations: as RA, SLE, raynaud

phenomenon
Polyarteritis nodosa
 One of several autoimmune dx dominated
by generalized bld vessels inflammation

 1/3 of pt caused by hep B infection and

associated with inflammation in vascular wall
owing to deposition of immune complexes (
type3 hypersensitivity)

 Occur in young adults, present acutely,

malaise, fever, HTN, weight loss , renal failure
Inflammatory myopathies
 Varied grps of disorders characterized by
autoimmune skeletal muscle injury that
occur alone with other autoimmune dx

 Features: muscle weakness, sreness,

fatigue, lymphocytic inflammatory cell
infiltrates in affected muscle grp

 Lab evidence of autoimmune dx

Immunity in organ and tissue
transplantation
 Transplantation: donor and recipient
should be matched to avoid immune
reaction except identical twins

 The best donor matches of MHC antigens

and bld groups
Immunity in organ and tissue
transplantation
 Hyperacute organ rejection:
- reaction that occurs in the operating
room as the surgeon connects the organ
to the recipients vascular supply

- It occurs when preformed antibodies in

recipient bld react immediately with graft
endothelial cell producing vessel
thrombosis ( immediate removal)
 Immunity in organ and tissue
transplantation
 Acute organ rejection:
- Within few weeks owing to an imune vasculitis

 Chronic transplant rejection:

- Develop months- years
- Dt variety of immune reactions; not
understood
- Antibody- mediated vasculitis can lead to
ischemia and hypoperfusion that slowly starves
the donated organ
Immunity in organ and tissue
transplantation
 Graft versus host disease is a devastating
complication in bone marrow
transplantation

 Manifestations: severe dermatitis, diarrhea,

jaundice , death from infection
Immunity in blood transfusion
 It’s a form of temporary tissue
transplantation
 Successful bld transfusion depends on
RBC compatibility between donor and
recipient

 Transfusion reaction is a complication of

bld transfusion during which there is
abnormal response to transfused bld
Immunity in bld transfusion
 2 types of transfusion reaction:
- Major of antigenic incompatibility btw
infused rbc and pt plasma agglutinin ; so
they do cross match (major, minor)
- Minor reaction of various type
little danger in transfusing imcompatible
plasma
Amyloidosis
 Abnormal form of normal protein
 Dysfunction result from systemic
deposition of amyloid protein
 Formed when normal protein is folded
into abnormal, crystal like molecules,
deposited between cells in interstitial
tissue
 Amyloid appear as transulent, smooth,
glassy material
amyloidosis
 Causes: autoimmune disease or chronic
infection
 Amyloid deposit in liver and adrenal gland,
glomerulus , myocardium, nerves, brain
 This deposition cause dysfunction

 Amyloidosis can be hereditary

 May occur in some tumors islets of
langerhans with type 2 DM
 No cure, average survival few years
Immunodeficiency diseases
 Dt deficiency of T cell or B cell origin
 Inherited or acquired
 Apparent after infection

 Patient with B cell deficiency do not produce

effective antibodies so suffer from infection

 Patient with Tcell deficiency also prone to

infection and to development of neoplasm dt
failed immune surveillance

 In immunodeficiency the infection is opportunistic

 Inherited immunodeficiency disease

 X linked agammaglobunemia (bruton dx)

result from failed embryonic B cell
development ; so pt do not produce
antibodies
 T cell no affected
 Age: 6 months cz the passive immunity wanes
 Symptoms: recurrent infections, bronchitis,
pneumonia, sinusitis, pharyngitis, ear, GIT inf,
some develop autoimmune dx
Inherited immunodeficiency disease
 Thymic hypoplasia( digeorge syndrome)
embryonic failure of T cell development ,
B cell immunity is unaffected

 These pt suffer from, viral, fungal,

protosoal infections , no parathroid and
may have anomalies of neck, face, ear,
neck, aorta
Inherited immunodeficiency disease

 Most common immunodeficiency is Ig A

present in GIT and respiratory tract
nomally
 Deficiency result in infection
Inherited immunodeficiency disease
 Most severe SCID( severe combined
immunodeficiency)
 Group of inherited diorders affecting B and
T cell fct
 Cause: single gene defect, X linked affects
male
 In SCID lymphoid tissue and thymus
underdeveloped and bld lymphocyte is
always low
 Symptoms: infections pneumocystitis, candia,
opportunistic infections
Acquired immunodeficiency
syndrome (AIDS)
 Most immunodeficiency's are acquired
- AIDS (most serious)
- Malnourishment
- Hodgkin lymphoma
- Sarcoidosis
Acquired immunodeficiency
syndrome (AIDS)
 Caused by human immunodeficiency virus
(HIV) which infect lymphocytes and brain
cells

 Associated with infections, secondary

neoplasms and neurologic disease
Acquired immunodeficiency
syndrome (AIDS)
 criteria for diagnosis of AIDS
- Lab abnormality
- Presence of certain infections, malignancies

 CDC criteria :
- Peripheral bld CD4 +lymphocyte count<200 c/microl
- Or other lab evidence of HIV infection (HIV antigen
or AB)
- And reccurent infections
- Or progressive multifocal leukoencephalopathy
- Or certain types of neoplasms
- Or severe wasting
criteria for diagnosis of AIDS
 Among adolescents; 5 grps, in descending
order of risk:
- Homosexual or bisexual males
- IV drug abusers
- Pt with hemophilia
- Recipients of rbc transfusion
- Heterosexual contacts of the above : HIV
carried by lymphocytes in semen
- Needle stick (shared)
- In utero
Etiology and pathogenesis of AIDS
 Once virus inside T lymphocyte, HIV
produce abnormal DNA that merge with
normal DNA
 Corrupted DNA produce new HIV
particles using pt infected T lymphocytes
as HIV factory
 New HIV virus exit the cell to infect and
kill other CD4 T cells until cycle continue
 T cell devastated and pt die from AIDS
opportunistic infections or malignancy
Etiology and pathogenesis of AIDS
 Some CD4 cells do not die remain
inactive cell
 T cell is the responsible but B cell system
is also adversely affected, stimulated by
HIV antigen, CMV, EBV and other
infections that occurs in AIDS

 Stimulated B cell produce large ammount

of antibodies but they are inffective as
defense mechanism
Natural progression
 Diagnosis:
- CD4 T cell count <200 cell/cumm
 Pt is asymptomatic immediately
 After few wks: flu syndrome
Malignancies of immune cells
 B and T lymphocytes can be malignant
 Classified in 3 groups:
- Lymphoma
- Lymphocytic leukemia
- Plasma cell proliferations