IMMUNOLOGY 2024

From A to Z
From M to U

Lecture 1: Page 2
Lecture 2: Page 13
Lecture 3: Page 23

Mohamed Mahmoud Tasneem Mansour

Kareem Arafa Nouran Adel
Mahmoud Gaber Mayar Magdi
 Innate immune system
there is a difference between immunity and immunology :
• Immunity is protective part of immune system (immune system protect
individual after vaccination or infection)à good
• Immunology: but not every reaction of immunity is protective.
o If absent will cause immune deficiency
o If overactive will cause hypersensitivity Disease state

Individuals born with inherited form of innate immune system from their
parents which is very effective in the first 6 months of life protecting him until
the individual develops his own immune system.
Any deficiency of innate immune system is lethal. However, human can live
with a non-working part of acquired immunity (even thymus gland we can
still be alive without it as it disappears at teen age). So, deficiency of innate
immune system is lethal and incompatible with life but deficiency of
acquired immune system can lead to diseases which maybe autoimmune
or hypersensitivity reaction.
Toll-like receptors (TLR)
TLR is an important part of the innate immune system which are present on
the surface membrane of the macrophages.
TLR has 13 subtypes, each one binds to certain structures which called
“pathogen associated molecular patterns” (PAMPs).
As human beings are exposed to infections by bacteria, viruses or parasites,
these microorganisms are counteracted by the innate immune system
(especially macrophages) and divided, hydrolyzed, and broken down to their
original structures as DNA, RNA, and lipopolysaccharides (the essential
structures of microorganisms).
Each TLR bind to a certain structure of these organisms through receptors on
the surface membrane of the macrophage → they cause changes in the
receptor → intracellular transmission of the stimulus → activate transcription
factors → activate parts of the gene → produces gamma interferon,
bactericidal enzymes to kill the organism.
There are recent applications of TLR in competing infections, treatment skin
cancer and Alzheimer’s disease.
TLR may be surface membrane receptors (extracellular) or
intracellular receptor.

‫ اﻟﺒﺎﻗﻲ ﻛﺎن ﻓﻲ اﻟﻮرق اﻟﻠﻲ اﺣﻨﺎ ﻣﻄﺎﻟﺒﯿﻦ ﺑﯿﮫ ﻓﺎﺣﻔﻈﮫ ﺑﺮﺿﻮ‬، ‫اﻟﻠﻲ ﺑﺎﻻﺻﻔﺮ اﻟﻠﻲ اﺗﺸﺮح‬

Extracellular TLR (Binds to bacteria only).

Receptor ligand Ligand location
multiple triacyl lipopeptides (soluble Bacterial
TLR 1
factors from bacteria) lipoprotein
Heat shock protein (HSP 70) 1 Host cells
multiple lipopeptides and proteolipids Bacterial
multiple glycolipids peptidoglycans
TLR 2 lipoteichoic acid Gram-positive bacteria
zymosan (Beta-glucan) Fungi
2
HCV core, nonstructural 3
proteins
lipopolysaccharides {LPS}4 Gram -ve bacteria
TLR 4 several heat shock proteins Bacteria and host cells
fibrinogen host cells
 heparin sulphate fragments host cells
hyaluronic acid
TLR 5 bacterial flagellin bacteria
Multiple Diacyl lipopeptides Mycoplasma
3
TLR 6 Zymosan (which is used in
stimulation of cell in vitro).
1- is chaperones protein released from ribosomes and causes familial
Mediterranean fever (FMF)
2- HCV has 4 genotypes (1, 2, 3, and 4) HCV genotype 4 is the worst
genotype and is common in Egypt.
3- TLR2 and TLR6 combine with each other
4- LPS the virulent factor of gram-negative bacteria which causes
septicemia, meningococcemia, and death.
Intracellular TLR (Mainly viral)
Receptor ligand Ligand location
Double stranded RNA (dsRNA)
TLR 3 virus
,poly I:C
single stranded RNA (ssRNA)5 RNA viruses
imidazoquinoline
small synthetic
TLR 7 loxoribine (a guanosine analogue)
compounds
bropirimine
resiquimod
small synthetic compounds; single
TLR 8 stranded viral RNA (ssRNA),
phagocytized bacterial RNA(24)
unmethylated CPG (cytosine-
TLR 9 phosphate-guanine) Bacteria, DNA viruses
Oligodeoxynucleotide DNA.
TLR 10 triacyl lipopeptides (as TLR 1)
Bacteria (E.coli ,
flagellin (as TLR 5) 6
TLR 11 salmonella)
Profilin Toxoplasma gondii 7
TLR 12 profilin Toxoplasma gondii
Bacterial ribosomal RNA
sequence (CGG AAA GACC) but
TLR 13 Virus, bacteria
virus, and bacteria not the
methylated version.
5- Patients who die from severe COVID (RNA VIRUS) infection was found
to have congenital deficiency of TLR 7.
6- Duality of the system: means that each function in immune system is
carried on two ways. E.g. flagellin is bound by TLR 5 and TLR 11 so if one
is defective the other will work, but not with the same efficiency. Even the
function may differ, e.g. when excess flagellin binds to TLR 5 which stimulate
the process (switch on). After saturation of the receptor, the reminder part bind
to TLR 11 leading to inhibition/switch off of the process
7- Toxoplasma is a single organism that lives in neuronal cells which change
the behavior of human beings and cause schizophrenia and invade the brain
when the immune system is suppressed as in HIV. Toxoplasma makes the
mouth unafraid from the cat and the monkey unafraid from the tiger to eat
them and continue its sexual cycle; because the male and female gametes of
toxoplasma mate only in cat families so they can replicate and make genetic
variations to improve generations & continue their invasion to the world
(toxoplasma replicate asexually by binary fission in hosts other than cats
which has no genetic variations).
Þ TLR 10, 11, 12, 13 bind to protist. Protist is a single-celled organism
of the kingdom Protista, such as a protozoan (parasites) or simple alga.

Applications of TLR
TLR 4 antagonists are being developed to beneficially block TLR 4 signals
and its action on LPS. It is used in conditions such as sepsis, septic shock,
lung inflammation and rheumatoid arthritis.
Mycobacterium tuberculosis suppresses the macrophage phagocytic activity
by 10 ways and replicate inside it. Host directed therapy (HDT) is a recent
approach in the treatment of TB through enhancement of macrophage
function in TB patients (activating cell of individual to do this job not to kill the
mycobacterium). This approach is meant to replace conventional anti-
mycobacterial therapy (AMT).

Toll-like receptors (TLRs), which serve as a bridge between innate and

adaptive immunity, may be viable treatment targets. TLRs are the first line of
defense against microbes and activate signaling cascades that induce immune
and inflammatory responses. Patients with "hot" versus "cold" tumors may
respond more favorably to immune checkpoint inhibition, and through their
downstream effects, TLR agonists have the potential to convert "cold tumors"
into "hot tumors" making TLRs in combination with immune checkpoint
inhibitors, potential targets for cancer therapies. Imiquimod**(MCQ) is a
topical TLR7 agonist, approved by the FDA for antiviral and skin cancer
treatments. Other TLR adjuvants are used in several vaccines including Nu
Thrax, Heplisav, T-VEC, and Cervarix. Many TLR agonists are currently in
development as both monotherapy and in combination with immune
checkpoint inhibitors. In this review, we describe the TLR agonists that are
being evaluated clinically as new therapies for solid tumors.
HLA
Human leukocytic antigens (HLA) are surface membrane proteins which are
coded by genes on chromosome 6 (MHC genes).
HLA has 2 classes:

Class I Class II
• Major transnational • D and its subtypes (DR,
antigen: A, B and C DP, DQ)
Types
• Minor transnational • The new types of DM and
antigen: E, G and F TAP
All surface membrane of Present only in immune cells
Present in
nucleated cells. (T and B cells)
• Formed by one α-
peptide and bound non-
covalently to B2
micro-globin (B2M)1 • 2 peptides α and β peptides
• α-peptides fold into 3 everyone has 2 domains.
extracellular domains • α1, α2, β1 and β2
Structure
(α1, α2, & α3). • Foreign peptides bind to α1
• Foreign body (peptide) and β1.
bind between α1 and
α2 domains.
• Foreign antigen must
be in peptide form
 (broken down by the
action of macrophage)

• Class I (A, B, and C)

are used in matching
for transplantation.
Function • Class I is called Immune response antigens
transplantation
antigens (control
transplant rejection and
acceptance)
Both have intracytoplasmic part which pierce lipid bilayer
membrane to involve in intracellular interactions

1- B2M is a tumor marker found in lymphoma and in some diseases of the kidney.

Each HLA Types has associated

diseases. These antigens are inherited
in Co- dominant inheritance
Codominant inheritance: mean to
inherit e.g: HLA-A , HLA-B ,HLA-C
from parents& express them all ,e.i :
all inherited genes are expressed
HLA system is the most
pleomorphic (not polymorphic )
genetics system in the world. e.g :
HLA-A class has e.g. 50 type of
alleles (different alleles at the same
locus ).These can be seen in
multiparous women where different
new Abs are formed against HLA of
the baby.
 Disease susceptibility d.t presence of certain HLA genes

1
2

v Most diseases are associated with class 1 (especially B)

1. Ankylosis spondylitis B27 (sacroiliitis)
2. Reiter’s disease B27 (knees & eyes )
3. Behcet’s syndrome B5 (or sometimes call 52)
4. BW15 (not definitive , still working on it)
v B8 is the most associated with diseases
 Can HLA gene be protective ?
Yes ,and the most common example is protective system against malaria
v A large case-control study of malaria in West African children shows that
a human leucocyte class I antigen (HLA-Bw53) and an HLA class II
haplotype (DRB1 *1302-DQB1*0501), common in West Africans but rare
in other racial groups, are independently associated with protection from
severe malaria.
v Another example of protection is survival of covid :
HLA-A*68 was found to be a protective allele against the severe infection and
fatal outcome , HLA-DRB1*03 also appears to be a protective factor against
fatal outcome, however, the low frequency of this allele in the studied
population limits the statistical power. The severity and fatal outcome of
COVID-19 patients in Tapachula, Chiapas depend more on the lack of
resistance than susceptibility HA alleles.

Macrophage
Macrophage is one of the most important cells in innate immunity.
They are tissue resident cells that develop from circulating (peripheral
blood) monocytes.
They are crucial unique cells as they can produce the molecule ( enzyme ) &
its opposite ( anti - enzyme ), e.g. they secrete coagulation factors and tissue
plasminogen activators.
N.B. Microphages = polymorphs
The name of the macrophage is acquired from the tissue it resides , as :
⋆ Macrophages of brain : dr :astrocytes (Microglia ,google )
⋆ Macrophages of bone : Osteoclasts.
⋆ Macrophages of liver : Von Kupffer cells.
⋆ Macrophages of skin : Langerhans.
⋆ Macrophages of circulation : Dendritic.
⋆ Macrophages of lung : Alveolar (pulmonary) macrophages.
⋆ Macrophages of spleen :
(red marrow ): Red bulb macrophages ,(White marrow) : white bulb
macrophage.
It is a cell of multiple functions. It’s phenotyped according to :
1. Surface marker M1 , M2 , M tumors {TAM} (tumor associated
macrophages ) , M obesity {ATM} (adipose tissue macrophages)
2. Secretions it secrets , It secretes a lot of products most importantly :
v Radicles :
1- Reactive oxygen intermediate ( ROI) :O2 radicles , hydrogen peroxide
(H2O2) , (Hydroxyl Radicles (OH) ,google)
2- nitrogen intermediates e.g : NO
v low molecular peptides: PG , leukotrienes , lipoxins
v cytokines : low molecular weight peptide secreted by a given cell , either
to act on the same cell: Autocrine effect , or a nearby cell : Paracrine
effect , or a distant effect :Endocrine effect (e.g : IL-1 & TNF cause
fever )
- If released from monocyte :Monokines , if from lymphocyte : lymphokine
, if from WBC to affect another WBC: Interleukin (there are 270- 280
different interleukin)
- So , every phenotype of macrophages secrete different sets of metabolites,
which controlled by Th1 & Th2 .
- Macrophage is cell acting as a gland , it transform to epithelioid cell in TB ,
or inflammatory granuloma with loss of phagocytic activity to be a more
secretory cells (epithelioid cells )
- It also may transform to tumoricidal cells macrophages killing tumor cells .
- It secrete enzymes & anti enzymes at the same time this is controlled by its
specific secretagogue (Th1 ,….) & its amount (to release or inhibit enzymes)
E.g : it secretes coagulation factors like TPA simultaneously with secretion of
prothrombin
 Memorize all

In the center, Naive macrophage (or monocyte) ,which didn’t change to

different types of macrophages. Under the effect of LPS / INF-Y will
transform to M1.
M1 macrophages secrete : Reducable NO intermediates , IL-1b , IL-6, IL-12,
TNF alpha and express on the surface CD11c , CD80 , MHC-2 , CCL-2
Which are chemokines which mean :cytokines that attract other cells
CCL mean :Cystine – Cystine – ligand
CXCL : cystine -X- cystine – Ligand (different AAs)
Chemokines :cytokines that cause attraction to other cells :
• CCL-2
• CXL-9
• CXCL-10
M1 Macrophages is activated by LPs ,INF-Y released by Th1
M2 Macrophages is activated by IL-4 , IL-13 released by Th2
M2 macrophages secrete: Arg-1,IL-4, IL-10, IL-13, TGF- B CD163, CD204,
CD206 ,CXCR1, CXCR2, CCR2
Macrophage in cancer have different phenotypes from in obesity
MCQ “previous year Question “ :surface receptors of tumor in obese
patient
The only macrophage that have IFN-Y is macrophage of obesity
Obesity macrophages has similarity with M1 macrophages (IL-1B, IL-6,
IFN-y, CD36, PPAR-Y, Term-2) but has IFN-Y which is anti-tumor.
- TAM secrete: IL-10, TGF-B, INE-d, CD163, CD204, CXCL-8, CCL2,
CCL5, CD24, CD47. CXCL-8 is unique to tumor macrophages .

Macrophage Activation Syndrome ( MAS )

v Laboratory findings :
• Thrombocytopenia ( ≤ 262 , 000 / µL )
• Glutamic oxaloacetic transaminase ( > 59 U / L )
• Leukocytopenia ( ≤ 4 , 000 / µL )
• Hypofibrinogenemia ( ≤ 2.5 g / L)

v Clinical findings:
• Central nervous system symptoms : seizures , coma , pain , irritability
• Hemorrhagia :purpura , hematoma , mucosa bleeding .
• Hepatomegaly

v Histopathology :
• Hemophagocytosis in bone marrow ( Diagnostic )

v Diagnosis:
- Diagnosis needs at least two laboratory criteria or two clinical &/or
laboratory criteria
- Bone marrow puncture is necessary in uncertain cases only
There is a difference between increased susceptibility to infection &
immunodeficiency. Could there be increased susceptibility to infection without
immunodeficiency? yes
Warning signs of increases susceptibility of
Increased susceptibility to
infection: infections may be in many
different forms (manifestations):
• +ve family history
• 2 attacks of pneumonia per one year with 1- virulent organisms
two difference lobes or lungs (if in the same 2- commensals become virulent
lobe , it’s a local problem d.t bronchial d.t immune suppression
obstruction ) 3- recurrent infections
• 2 serious sinus infection (severe sinusitis &
4- infections in uncommon sites
septicemia etc..)
• A course of 2 months of IV antibiotics to 5- delayed resolving infections
control the infections. 6- atypical infection
• Deep seated infections (e.g. in the deep
fascia of thigh)
• 8 otitis media
• 6 attacks of common cold per year
Immune deficiency without increased susceptibility to infection :
1- Complement deficiency:
Complement: pro-pre-enzymes plasma proteins which activated through:

A- classical pathway : this pathway activated by IgG &IgM (IgM> IgG, IgG1= IgG3
>IgG2, IgG4 doesn’t activate complement , rest of IgA,IgD & IgE : does’t activate
the complement) , and then complement activate each other in sequence.
Deffieciency in this pathway doesn’t necessarily ­ susceptibility to infection.

B- alternate pathway : Another way of activating complement by factor P & F.

Deficiency of this pathway always leads to ­ susceptibility of infection that may be
life threatening .
C- Manan binding protein (MBL) pathway: Manan is a polymer of mannose sugar,
lectin is the protein which binds complement to the sugar.
N.B: Complement system has controlling proteins to control these pathways
N.B: C1 is activated (divided) by C2 to 3 fragments (C1Q,C1S,C1R) These
fragments activate other complements in sequence

à Complement deficiency leads to :

1- C1 (the whole complement ) deficiency à SLE (autoimmune dx not infection)
2- C1Q deficiency à cerebritis, special form of SLE (deficiency of a component
leads to more severe form than deficiency of the whole complement)
3- C1INH(inhibitor) its deficiency à hereditary angioneurotic edema
4- C2&C4 deficiency à SLE
C6,C7,C8 are called HIT
5- C3 deficiency à recurrent infection SEQUENCE à bind the
6- C5 deficiency à non specific autoimmune dx membrane of RBCS or
organisms leading to
7- C6,C7,C8 deficiency à life threatening gram hemolysis or death of the
-ve septicemia (meningococcal or gonococcal) organism ,they must be
8- C9 deficiency à PNH (paroxysmal nocturnal stabilized by C9 to fix be
hemoglobinuria) fixed to the membrane of
target organism

Immunodeficiency is classified to primary (15%) & secondary (85%)

Primary Immunodeficiency: congenital & less common:
1- B-cell deficiency (Ab deficiency ): pyogenic infection like skin infections,
abscesses ,otitis media, pneumonia and sinusitis , no viral infections
2- T-cell deficiency ( cell mediated deficiency): viral infections. and may be:

N.B: T-cell deficiency may be

• Congenital deficiency (DiGeorge syndrome): deletion in ch22 where there
is no thymus gland where T lymphocytes mature .
• Acquired deficiency: AIDs .
3- severe combined immunodeficiency (SCID): T&B cell deficiency, where there
are both bacterial & viral Infections.
4- Macrophage deficiency
5- Common variable immune deficiency (CVID): the only form of 1ry
immunodeficiency in adults
6- X linked gamma-globulineamia
7- IgA deficiency leads to allergy (asthma) more than Immune system viral
recurrent infections (bronchiectasis) infections :
HIVà affects CD4 Th
8- Anti epileptic drug. (may be phenytoin, google)
cells
9- Hyper-IgM immunodeficiency syndrome EPVà B-cell
10- Selective subclass Ig deficiency CMVà Macrophage
11- wiskott Aldrish Syndrome (WAS): combined T&B
cell deficiency. A triad of:
a-pneumonias
b- small platelets (cytoskeleton abnormality) less than 6 FL (bleeding after
umbilical stump removal and circumcision)
c- viral infection
secondary Immunodeficiency
1-DM(IMP)
2-Associated with some motor neuron lesion
3-nephrotic syndrome
4-plasma pheresis
5-protein loosing entropathy
6-solid tumors
7-CML (patient die d.t recurrent pneumonia)
8-burns (loss of large area of skin lead to loss of serum Abs
9- immune system infections (see above)
 Immune senescence
• Immune senescence means aging of the immune system.
• Early onset immune senescence occurs in young’s (progeria syndrome)

à Manifestations of immune senescence:

1. Aging of B-lymphocytes which produce antibodies.
• Diminished Specific antibody response to antigens or vaccinations (e.g.
typhoid, tetanus, meningococci vaccines)
• Increased auto-antibodies, but don’t cause autoimmune disease.
2. Aging of cell-mediated immunity
• Negative tuberculin test (although may have TB), lepromin test, and candida
test.
3. Depressed manifestations of inflammation like fever and ESR
4. Increase incidence of infections.
• UTI (incidence in elderly is 20 times than young). Presents in elderly with
confusion and disturbed conscious level (DCL) because:
o The organism produces uricase enzyme which acts on blood urea and results in
increase ammonia level in the blood.
o Bladder vesical wall is rich in blood supply which is connected to vertebral
vessels (posterior vertebrobasilar system), so ammonia reach brain easily.
• Increase incidence of pneumonia (5 times more than others).
5. Diminished reaction to allergens
6. Diminished transplantation response (rejection of transplantation is diminished
in elderly), so they have more acceptance for the transplanted organ.
DM
à Infections that only occur in DM:
1. Malignant otitis externa
• Occurs almost exclusively in diabetics (if happen in a patient search
for diabetes)
• May occur in normal patient but very rare (1:1000)
• Caused by Pseudomonas aeruginosa.
• Presents as severe ear pain and drainage/pus from the ear.
2. Mucormycosis zygomycosis (black fungus or rhinocerebral mucormycosis)
 • Occurs in diabetic with COVID19.
• Treated with antifungal or debridement
3. Emphysematous cystitis in gallbladder or urinary bladder by gas forming
organism leading to air & pyocele.
4. Fournier disease :is gangrene in the scrotum.
• A rare but deadly infection of the genital and perineum. Symptoms of
this infectious process include swelling to the genitals and perineal
area associated with significant pain and can reach up to gangrene.
à Why infections increase in DM?
1. Hyperglycemia is a good nourishing medium to flush infections.
2. Narrowing of vessels by premature atherosclerosis decreases blood supply,
so, WBCs cannot reach site of infection.
3. Decreased intrinsic phagocytic activity of polymorphonuclear cells.
4. Sensory peripheral neuropathy
5. Autonomic diabetic neuropathy (important)
à Common infections in DM (This list is not all inclusive):
• Carbuncle, recurrent stye (infection of eye lash) are common but nonspecific
for DM.
• Common skin infections in diabetics as carbuncle, trichophyton, tinea pedis/
versicolor, Ulcer , Acanthosis nigricans are also seen in diabetic patient skin
but not a type of infection.
• UTI
• Bullous diabeticorum
• Diabetic foot ulcers
• Osteomyelitis
• Necrotizing fasciitis
One case control study assessed prevalence of skin infections in adolescents with
and without type 1 diabetes:
68% of type 1 patients with diabetes had at least one cutaneous infection vs. 26.5%
of control subjects, The most common skin condition was xerosis (dry skin)
 Combined variable immunodeficiency (CVID)
Almost the only primary immune deficiency occurs in adults.
à Essential of diagnosis
• Frequent sinopulmonary infections secondary to humoral immune deficiency.
• Low serum immunoglobulin (IgG levels <5 g% is DIAGNOSTIC) and
deficient functional antibody responses (no specific antibodies are formed
against vaccine).
• Primary defect may be with B cells or T cells (T helper which help B-cells ,not
cytotoxic T cells).

à General consideration (MCQ)

• The most common symptomatic primary immunodeficiency disorder is
common variable immunodeficiency [1].
• A heterogeneous immunodeficiency disorder clinically characterized by an
increased incidence of recurrent infections [2] , autoimmune phenomena [3], and
neoplastic diseases [4].
• The onset is generally in early adulthood, but it can occur at any age.
• The prevalence of common variable immunodeficiency is about 1 in 25,000 in
the United States.
• Most cases are sporadic; about 10–20% are familial MCQ.
[1] Old name of CVID was agammaglobulinemia or hypogammaglobulinemia.
[2] As sinopulmonary infections due to humoral deficiency.
[3] Cytopenias: thrompocytopenia, leukopenia, anemia, or all.
[4] Gastric or colon cancer

à Symptoms and Signs

• Increased susceptibility to infections, especially with encapsulated organisms
[1]
, is the hallmark of the disease.
• Chronic lung disease is one of the most frequent complications of common
variable immunodeficiency. Virtually all patients suffer from recurrent
sinusitis, bronchitis, otitis, pharyngitis, and pneumonia are common infections.
 • Infections may be prolonged or associated with unusual complications such
as meningitis, empyema, or sepsis.
• Bronchiectasis occurs in at least 25% of patients with common variable
immunodeficiency and is a leading cause of morbidity. (MCQ)
• Gastrointestinal infections and dysfunction are commonly associated with
common variable immunodeficiency, and a sprue-like syndrome, with diarrhea,
steatorrhea, malabsorption, protein-losing enteropathy, and
hepatosplenomegaly, may develop in patients.
• Paradoxically, there is an increased incidence of autoimmune disease (20%)
(MCQ), although patients may not display the usual serologic markers.
• Autoimmune cytopenias are most common, but autoimmune endocrinopathies,
seronegative rheumatic disease, and gastrointestinal disorders are also
commonly seen. Lymph nodes may be enlarged in these patients, yet biopsies
show marked reduction in plasma cells[4].
• Noncaseating granulomas are frequently found in the spleen, liver, lungs, or
skin [2].
• There is an increased propensity for the development of B-cell neoplasms (50-
to 400-fold increased risk of lymphoma) and gastric carcinomas [3].

[1] Pneumococci or streptococci

[2] as sarcoidosis
[3] Due to presence of GALT (Gut-associated lymphoid tissue)
[4] That’s why they don’t have immunoglobulins

à Laboratory Findings
• The main for diagnosis is serum IgG <5 g%
• Assess serum quantitative immunoglobulin levels. All patients with common
variable immunodeficiency have a reduced serum IgG level[1]., and either
serum IgM or IgA or both are reduced as well.
• Demonstration of functional or quantitative defects in antibody production is
ESSENTIAL and is typically performed by checking antibody response to
polysaccharide (Pneumovax-23) and protein antigens (such as tetanus and
diphtheria).
[1] Must have reduced IgG
 • The diagnosis is made in patients who have reduced serum immunoglobulins
and poor antibody response to vaccines, after exclusion of secondary causes
(eg, proteinuria, protein-losing enteropathy, drug effects such as rituximab
and other immunosuppressants, antiepileptics, and hematologic
malignancies) (MCQ).
• The absolute B-cell count in the peripheral blood can be normal. A subset of
these has concomitant T-cell immunodeficiency with increased numbers of
activated CD8 cells (MCQ), splenomegaly, and decreased delayed-type
hypersensitivity

à Treatment
• Replacement by IVIG for life 300 or 600mg/kg every 4 weeks (may be SC)

IVIG
Immune potentiation Replacement Supportive
USE
(modulator)
Dose:1-2g/Kg twice or 300-600mg/kg for
dose
thrice. life every 4 weeks
o ITP (most common
indication for IVIG)
o Guillain-Barre
syndrome (the
second most
common indication
for IVIG) Elderly patient with
CVID
indications o Takayasu arteritis pneumonia
o HIV
o Multiple sclerosis
(MS)
o Steven Johnson
syndrome in
necrotizing
neutropenias.
à Complications of IVIG
• Anaphylaxis due to IgA deficiency.
• Acute renal failure may be due to
o Sucrose contamination which causes osmotic effect on renal
circulation (Jewish hypothesis).
o organic mercurial toxicity by thiomersal (The preservative used in
IVIG preparation) (Dr. Serag hypothesis).
• Transmission of infections :mainly prions disease “Creutzfeldt-Jakob
disease; Cow mania” (HIV and hepatitis are normally screened during
preparation)
 Continue LEC 2

à Non- AIDS associated HIV conditions:

-occur when HIV patient doesn’t reach AIDs state d.t treatment. The patient can be
affected by other diseases like:
- leukemias
- cardiovascular diseases
- lipid problems
- certain tumors
(for more details ,see previous year notes )

à Post exposure prophylaxis:

Important especially in medical professions , where infection exposure is common
(especially through needle stick). Possibility of infection transmission increases when
:
- the needle in deep vein or deep artery
- the needle is contaminated with blood
- high viral load in the patient (> 650 copies/ ml)
The patient should start the treatment immediately after exposure (maximum within
72h from injury) and take it for 4 weeks.
 LEC 3: Hypersensitivity reaction
It thought to be 4 or 5 types discovered by (Gell ,Coombs ) 1973 + Landsteiner
( ‫)ا ﻟ ﻤ ﻨ ﺴ ﻲ‬

Classes of hypersensitivity:
1. I
2. II
3. III
4. IV

The new classification:

1. I : anaphylactic reaction/ IgE dependent reaction/ immediate reaction , ex:
anaphylaxis , food allergy
2. II :cytotoxic reaction (autoimmune diseases)
3. III : immune complex reaction ( the cause of all rheumatological diseases )
4. IV : no Ab reaction of cellular organisms ex: TB , leprosy , dermatitis
A. IVa : Th1
B. IVb : Th2
C. IVc
D. IVd
5. V ( subtype of type 2 )

The original concept that T& B lymphocytes are the primary cells of acquired
immune system, nowadays, there is a group of T lymphocytes which belongs to the
innate immune system ( innate = born with it ) which called ” innate lymphoid cells
(INCs) “,they are divided into 3 groups:
1. Like type Th1
2. Like type Th2
3. ‫ﷲ اﻋﻠﻢ‬

INCs is the cause of the new classification of hypersensitivity reaction .

 6 5

2 8

4 7
9

1- types of allergen : inhaled , food , injected allergen

2- basophil also can be activated
- for Mechanism of mast cell activation, see next page
3- The antibody is IgG (at the past was IgG and IgM)
4- other examples:
a- against cell Ag: autoantibodies against thyroid, autoantibodies against stomach ,
autoantibodies against red cells (autoimmune hemolytic anemia)
However, in autoimmune hemolytic anemia, the autoantibodies is not against
RBCs Ag, but against external chemicals (Hapten) intimately related to red cells.
b- against matrix associated Ag: Tissue antigen example: atrophic gastritis
,antibiotic cell antibodies ,autoimmune cytokines
5- The mediators are TH2 cytokines (IL-5,IL4/IL-13) , mimic type I
6- The mediators are TH1 cytokines (IFNY , TNF alpha ), mimic type II
7- IgG , soluble antigen ,FcR cells complement (like type 2 ) but the difference is
that here it causes vasculitis sickness , Arthus reaction (injection of serum {foreign
antigen} into the skin of an experimental animal “rabbits” lead to reaction after few
days{not in humane })
8- Causes febrile neutrophilic syndrome
9- AGEP (Acute Generalized Exanthematous Pustulosis), it’s one of the febrile
neutrophilia (febrile neutropenia another more serious condition) especially in
patients who receive chemotherapy or cytotoxic drugs, it is particularly serious
when WBCs < 500 )
- AGEP : is a rare, acute eruption characterized by the development of numerous
non follicular sterile pustules on a background of edematous erythema Fever and
peripheral blood leukocytosis are usually present.

N.B In type IV, mediators are not Antibodies

Mechanism of mast cell activation :

A- IgE Cross linking to mast cells (classical):
-Receptor of IgE bonded to mast cell, when 2 IgE transmite 2 signals à activation
of mast cells à release of mediators :
1- preformed : histamine, enzymes
 2- Newly formed mediators: leukotriene , cytokines , prostaglandin

-The distance between the 2 limbs of IgE : is 6 angstrom (Å), So any antigen larger
than 6 Å can cross link the IgE à stimulation of secretion of mediators from the
granules, not degranulation which means release of all granules inside mast cells
:
- Secretion à bronchial asthma
-Degranulation à anaphylaxis

N.B. The process become more complicated not just cross linking of mast cell
bound IgE but there are 3 or 4 different mechanisms for mast cell activation.

B- Complement receptor mediated :

Anaphylatoxin Complement ( C3a ,C5a ) à stimulation of mast cells
e.g. Allergy to drug product not IgE but complement mediated
C- Mast cells related G protein ( MRGPRX2 )
D-Unknown organism
e.g. Allergy of non-steroidal anti-inflammatory
Anaphylaxis
General Considerations
• Anaphylaxis is the most serious and potentially life-threatening manifestation of
mast cell and basophil mediator release (mainly basophils).
N.B. release : occurs in uncontrolled manner.
• Anaphylaxis is defined clinically under the following circumstances:
1. an allergen exposure followed by the acute onset of illness involving skin or
mucosal tissue and either respiratory compromise or hypotension (systolic
blood pressure less than 90 mm Hg or 30% less than known baseline)
2. A likely allergen exposure followed by the acute onset of two or more of the
following conditions: skin or mucosal tissue involvement, respiratory
compromise (laryngeal stridor or bronchial asthma) , hypotension, and
persistent (not transient) gastrointestinal symptoms; or
3. (the earliest) a known allergen exposure followed by hypotension.
• Anaphylaxis may be
1. IgE dependent anaphylaxis and in diagnosis search for IgE; and
2. Non IgE dependent anaphylaxis and there is no IgE.
• IgE-dependent anaphylaxis is usually an acute syndrome initiated by a new
allergen exposure after a prior silent exposure has sensitized the patient with IgE
antibodies.
• Thus, anaphylaxis (or systemic allergic reactions which do not meet the definition
of anaphylaxis) cannot occur on first-time exposure to allergens like drugs,
insect venoms, latex, and foods. In contrast, other syndromes of anaphylaxis
(sometimes called “anaphylactoid”), such as reactions to radiocontrast media
and most NSAID and opioid reactions, are pseudo-allergic without known
immunologic mechanisms and can occur with first-time exposure.

Clinical Findings
A. Symptoms and Signs
• Symptoms and signs typically occur within 30 minutes of initial exposure
(immediate reaction) but may appear up to several hours later (delayed
reaction).
• Anaphylaxis may be immediate or delayed.These include (in order of
frequency):
1. Skin manifestations (most common): typically, urticaria but also flushing,
blotchy rashes, and pruritus (palm and sole pruritus).
2. Respiratory distress, including wheezing, stridor, bronchospasm, and airway
angioedema.
3. Gastrointestinal symptoms, including cramping, emesis, and diarrhea
(especially in food allergy).
4. Hypotension, often manifested as lightheadedness, dizziness, or syncope.
The condition is potentially fatal, especially if untreated, and can affect both
nonatopic and atopic persons.
5.
Risk factors of anaphylaxis
Patient taking Beta blockers if exposed to anaphylaxis may die.
B. Laboratory Findings
• Identification of anaphylaxis is clinical as the need for treatment is urgent.
• Elevated serum levels of mast cell mediators, such as tryptase and histamine,
may be detected shortly after a reaction providing support to the diagnosis
(Support not diagnostic. Diagnose is mainly clinical).
• Referral to an allergy specialist is standard because of concern for a future
reaction and need for appropriate interventions and education.
C. Investigations
1. Specific IgE serum
2. Histamine
3. Fluid IgE serum
4. Skin testing (important).
o Skin testing, which is usually more sensitive (than specific IgE), may be
performed to suspected allergen.
o Optimally occurs 4–6 weeks (wait 4-6 w before the test) after a severe
reaction to avoid falsely negative testing during a postreaction “refractory”
period.
o The positive predictive value of these tests is highly dependent on a
suggestive temporal relationship to putative allergen exposure.
Treatment
• 2 doses of IM EpiPen® is the most important treatment.
A. Preloaded epinephrine.
B. Don’t use SC.
C. And never use IV(contraindicated) because it is fatal.
• Early administration of I.M epinephrine (in the ant. Part of the thigh) at the
onset of suspected anaphylaxis is the cornerstone of therapy.
• Supportive measures, such as oxygen, intravenous fluids and, if required,
airway management are also appropriate.
• Adjunctive pharmacologic therapies include antihistamines, bronchodilators,
and corticosteroids.
• Self-administered epinephrine at the earliest signs of recurrence can be life-
sparing, whereas antihistamines and corticosteroids have limited value in
reversing anaphylactic syndromes.
 Food allergy
Adverse reaction to food may be toxic or non-toxic.
A. Toxic
1. Infection: by staphylococcus aureus, or
2. Chemicals: A common example is mercurial toxicity in wheat in 80S.
B. Non-toxic (more important):
1. Nonimmune:
• Enzymatic deficiency:
o Lactase deficiency (most common): milk ingestion, and common in
Africans.
o Sucrase deficiency: causes GIT disturbance after sugar ingestion.
o Caseinase deficiency: Caseinase normally catalyzes casein found in milk
• High level of vasoactive amines: the food which is nonallergic becomes allergic
o Scombroid toxicity (High Histamine Content Of Ingested Fish)
§ Defrosted fish then refrozen.
§ Defrosting fish leads to decomposition and release of high levels of
histamine then, fish will be refrozen with high level of histamine which
result in toxicity.
§ GIT manifestations occur due to high histamine content of the ingested fish.
o Another toxicity by fish: (without allergy)
§ When fish are infested by pinworms causes diarrhea.
o Feeding dead chicken bone for fish in fish farms as a source of protein.
Which Contains high level of cadaverines (vasoactive amines).
o High content of tryptamine (a vasoactive amine) in roquefort cheese.
o Excess drinking of coffee
• Food aversion: psychological dependence induces reaction on the sight of the
fish.
2. Immune:
• IgE dependent (true food allergy): must have IgE against certain food.
• Non-IgE dependent
• Mixed reactions :like dermatitis herpetiformis, and celiac disease (these
examples are non IgE dependent {google}, ‫) ﺑﺲ اﻟﺪﻛﺘﻮر ﻗﺎﻟﮭﻢ ﻓﻲ اﻻﺗﻨﯿﻦ‬
Immediate allergic reactions within 2 hours of ingestion of foods are much less
common among adults (Disease of adult) than children. Most acute systemic food
allergy is caused by proteins in milk, egg, wheat, soy, fish, shellfish, peanuts, and
tree nuts
Milk and egg allergies in atopic children are often out-grown by adulthood.
Shellfish, peanuts, and tree nuts are the most common causes of food anaphylaxis
in adults (not out grown by childhood)
Diagnosis of food allergy relies on a combination of his-tory, skin tests (dr: no skin
test in food allergy), and serum specific IgE tests. There is no role for specific IgG
testing for evaluating food hypersensitivity. Because of frequent false-positive IgE
tests, especially among atopic patients, oral food challenge remains the gold
standard for diagnosis.
However, this procedure should only be conducted by an experienced provider in a
well-equipped setting (in hospital). Management involves strict avoidance of the
culprit food and guaranteed access to self-administered epinephrine(as food my cause
anaphylaxis first clinical manifestation)
Oral allergy syndrome (they have allergic rhinitis to free pollen), also known as
pollen-associated food allergy syndrome, is the result of cross-reactivity between food
and pollen proteins. Affected individuals have known seasonal pollen allergies (most
commonly tree pollens) and experience itching of the oral mucosa upon ingestion of
certain raw fruits (specially melons) and vegetables. In contrast to systemic food
allergy, symptoms are limited to the oropharynx and usually do not involve other
organ systems or progress to anaphylaxis. (ingested pollens may also cause
eosinophilic allergic esophagitis, gastritis, colitis & bronchitis beside causing allergic
rhinitis of OAS.
HLA Haplotypes & Risk of Delayed Onset Drug Hypersensitivity Syndromes
Activated cytotoxic CD8 T lymphocytes (MCQ) play a key role in the pathogenesis
of serious, drug-induced adverse cutaneous reactions, such as toxic epidermal
necrolysis. There are striking, medication-specific associations between inheritance
of particular HLA-B alleles and risk of these hypersensitivity reactions in defined
populations. Most notably, B∗57:01 confers risk for reactions to abacavir; B∗15:02
for carbamazepine; B∗58:01 for allopurinol; and B∗13:01 for dapsone.

Immune modulation:
Interference of immune system either to stimulate a depressed or depress an
overacting or to inhibit an allergen (toxinàtoxoid)
Best example: vaccination
o Clinical application : is immunotherapy of bronchial asthma (giving increasing
concentrations of the identified allergen (identified by skin test)
Rising concentrations as: 1/10000 à1/1000à 1/10
With dilution dose (of each concentration) :
Day o à0.3 mm of 1/10000
After 3 daysà0.5mm of 1/10000
After 3 days à 0.7 mm of 1/10000
After 3 daysà 1mm of 1/10000
Then repeat this with other concentrations till 1 cm (or 1mm??) of 1/10
Classical given SC & may be sublingual
Oral rout for food allergy. Bronchial route & nasal route are serious
o Mechanism (debatable):
1- May be change of Th2 to Th1
2- May be through (steric hinderance) on must cell surface between IgE & IgG
(As immunotherapy is IgG, it will hinder the binding of allergen to the IgE which
make mast cells not sensitive /responsive to allergen
o Sequence of response:
At first IgE increases, then IgE decreases & IgG increases (first increase in
IgG1&IgG3, then IgG4)
o Side effects:
1-local reaction
2-local skin infection at the site of injection
3-Anaphylaxis may be fetal d.t wrong vial (like giving 1/10 instead of 1/1000)
o Another new immunotherapy :
1-anti IgE
2-anti IL-5, anti IL2, anti IL4