Hahaha hajjanajaj

1. EKT
AJAJODIA
Immunodeficiency diseases

2. DEFINITION
It is the absence or failure of normal function
of one or more elements of the immune
system
Results in immunodeficiency disease

4. Immunodeficiency
Diseases
Primary: Usually
congenital, resulting from genetic
in some
of the immune
defects
components
system.
Secondary Acquired):
as a result
or
of other
conditions
diseases
such as:
»HIV infection
»malnutrition
»immunosuppression

5. PRIMARY
IMMUNODEFICIENCIES
Primary immunodeficiencies are inherited defects of the
immune system
They are classified according to IUIS , 2013

6. Combined immunodeficiencies
Combined immunodeficiencies with associated or syndromic
features
Predominantly Ab deficiency
Disease of immune dysregulation
Defects in phagocytosis
Defects in innate immunity
Autoinflammatory disorders
Complement deficiencies
INTERNATIONAL UNION OF
IMMUNOLOGICAL
SOCIETIES (IUIS:2013)

7. The B-lymphocyte/Antibody system
The T-lymphocyte/ cellular system
The Phagocytic system
The Complement system
The immune system functional compartments

8. INFECTIOUS DISEASES
AUTOIMMUNE DISEASES
GASTROINTESTINALDISEASE
HEMATOLYMPHOID DISEASES
Clinical Manifestations of the Primary
Immunodeficiency Diseases

9. INFECTIOUS DISEASES
An increased susceptibility to infection is thehallmark
of the primary immunodeficiency diseases (PID)
In most patients, this is manifested byrecurrent
infections

11. HEMATOL
YMPHOID DISEASES
Anemia, thrombocytopenia, or leukopenia are seen
frequently in patients with PID
Patients have increased chances of malignancy
especially of lymphoid organs

15. CELLULAR DEFICIENCIES

16. CELLULAR DEFICIENCIES
SCID and Combined immune deficiency
Wiskott-Aldrich syndrome
Hyper-IgM syndrome
Ataxia-telangiectasia
Di-George syndrome
Other primary cellular
immunodeficiencies

17. SEVERE COMBINED
IMMUNODEFICIENCY(SCID)
Fatal PID
Combined absence of
T and B lymphocytes
13 different genetic
defects that can cause
SCID

19. MOST COMMON TYPES
SCID
XSCID (X
linked )
Adenosine
deaminase
(ADA)

20. T-B+NK- phenotype SCID
Deficiency of common gamma
chain of TCR (X-SCID)
Deficiency of Janus kinase 3

21. Deficiency of common gamma chain of TCR
(X-SCID)
Common gamma chain (γc ) – a component shared by
TCR and other growth factor receptors
Mutation in gene encoding γc
Result in T-B+NK- phenotype
XR – so only males are affected

22. Deficiency of Janus kinase 3
Mutation in gene encoding Jak3
Required for function of γc
So phenotype is T-B+NK- ( same as X-SCID)
But this is – can affect both boys and girls

23. T-B+NK+ phenotype SCID
Deficiency of α chain of IL-7 receptor
Deficiency of CD3 chains
Deficiency of CD45

24. Deficiency of α chain of IL-7 receptor
Mutation in gene encoding IL-7Rα – a component of growth
factor receptor
T-B+NK+ phenotype
However, B cells do not function due to lack of T cells

25. Deficiency of CD3 chains
Deficiencies of the CD3 subunits (delta, gamma, epsilon, or
zeta) can cause an autosomal recessive form of SCID with a T-
B+NK+ phenotype. ... The T cell receptor complex consists of
the TCR heterodimer (alpha/beta or gamma/delta chain)
associated with four CD3 subunits (delta, gamma, epsilon,
zeta).
CD3 is a receptor complex on T cells and c/o :CD3δ ,
CD3ε and ζ-chain
3 forms of SCID are due to mutations in genes
encoding these 3 chains of CD3 complex

26. Deficiency of CD45
T-B+NK+ phenotype
CD45 deficiency causes a rare form of T-B+NK+
SCID which has been reported in a small number of
patients. ... CD45 is a transmembrane tyrosine
phosphatase involved in T cell receptor signaling and T
cell development in the thymus.
A deficiency of CD45 leads to a marked impairment in
T cell development.

27. T-B-NK- phenotype SCID
Adenosine deaminase deficiency
Reticular dysgenesis

28. Adenosine Deaminase deficiency
2nd MCSCID
Mutation in gene encodingADAenzyme
ADA is essential for T-cell function : Its absence cause
accumulation of toxic metabolites within lymphocytes that cause
cells to die
T-B-NK- phenotype

30. T-B-NK+ phenotype SCID
RAG1 and RAG2 gene mutation
Artemis deficiency
Cernunnos deficiency
Ligase 4 deficiency

31. Life threatening infections : most dangerous
organisms are-
1. Pneumocystis jiroveci
2. Chicken pox
3. CMV
4. Herpes simplex
Live vaccines
patients : they
should not be given to
may contract infection
SCID
from
vaccine viruses
So if family history of SCID is +ve : avoid live
vaccines

32. Diagnosis
Easiest way to diagnose:Absolute lymphocyte
count(ALC)
NormallyALC >4000/cu mm; 70% of which are T cells
SCID haveALC < 1500/cu mm
IfALC found low If
low again
Repeat test again specific
tests to be done to
count T cells and measure T cellfunction

33. COMBINED IMMUNODEFICIENCIES
Group of rare genetic disorders that result in combined
immunodeficiency but do not reach a clinical severity
level to qualify as SCID
7 types

34. Bare lymphocyte syndrome
Purine nucleosidase phosphorylase deficiency
ZAP70 deficiency
CD25 deficiency Cartilage
hair hypoplasia Coronin
1Adeficiency MHC classI
deficiency

35. HYPER IgE SYNDROME
Aka Job syndrome/ Buckley syndrome
Characterised by :
1. Recurrent eczema
2. Skin abscesses: particularly by S.aureus
3. Lung infection
4. Eosinophilia
5. Increased IgE levels

36. • autosomal dominant
• STA
T3 mutation (signal transducer
and activator of transcription 3)
• Connective tissue and
skeletal abnormality
• Typical facial appearance, hyper
extensibility of joints, bone
fractures after minor trauma
TYPE1
• AR autosomal recessive
• DOCK8 (dedicator of cytokinesis 8)
mutation
• Recurrent and severe viral infection
esp by herpes and molluscum
• Do not have connective tissue or
skeletal abnormality
TYPE2

37. Diagnosis
Increased IgE levels
Normal IgG,A,M
Increased peripheral blood eosinophils
HIES scoring system by National Institute ofHealth(NIH) :
Score : 0-15= unaffected
16-39= possibly affected
40-59= probably affected
>60 = definitely affected

38. Scoring system is esp for thediagnosis of Type 1
HIES (hyper IgE syndrome)
Definitive diagnosis : genetic analysisofST
A
T3 and
DOCK8 genes

39. WISKOTTALDRICH SYNDROME
Wiskott–Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder characterized by
the triad of eczema, thrombocytopenia, and severe and often recurrent infections.
TRIAD : In the histology of skeletal muscle, a triad is the structure formed by
a T tubule with a sarcoplasmic reticulum (SR) known as the terminal cisterna on either
side
1. Increased tendency to bleed: due to small,
dysfunctional and decreased number of
platelets
2.Recurrent infection
3.Eczema

40. Associated with W
AS gene mutation
Was gene produces W
AS protein (W
ASp)
If mutation is severe: complete absence ofW
AS protein :
known as classic WAS
If mutation is mild : some mutated W
AS protein present : known
as milder form of WAS

41. Diagnosis
1. Platelet abnormality : decreased number and small size : characteristic
2. Increased IgE
3. Sequencing of WASgene to identify mutation : definitive diagnosis
4. Determine WASprotein expression in blood cells

42. HYPER IgM SYNDROME
Inability to switch from production ofAb of IgM type toAbs of
IgG,Aor Etypes
Normal B cells can produce IgM on their own but require Help
from T cells to switch from IgM to IgG,A,E
HIGM results from defect in interaction between T and B cells

43. Genetic
defects
CD40L
def.
CD40
def.
AID
def.
UNG
def
NEMO
defect

45. CD40L (CD154) : deficiency of this ligand is themost
common form of HIGM syndrome
XR
So only boys are affected
Defect in NEMO gene : Known as ectodermal
dysplasia
Associated with sparse hair and conical teeth

46. DIAGNOSIS
Characteristic : failure to express CD40Lon
activated T cells – can be assessed by flow cytometry
CD40 L deficiency is due to mutation in CD40L gene
If gene is normal and CD40L is deficient : not HIGM
syndrome

47. So, for exact diagnosis : demonstration of CD40Lgene
mutation

48. ATAXIA TELANGIECTASIA
Mutation inA
TM gene (11q)
This gene is required for cell repair after DNAdamage
2 important presenting features:

49. • Abnormality in cerebellum
• Can be confused with
cerebral palsy(CP)
• In AT neurologic
deterioration occurs with
age (but not in CP)
• Needs wheelchair by 10-12
yrs age
A
T
AXIA
• Dilated and corkscrew shaped
vessels esp in white of eyes
TELANGI
ECTASIA

51. DIAGNOSIS
Clinical feature is very important but difficult to diagnose at
early age as telangiectasia occurs only by 5 yrs of age
Most imp test : AFP levels inblood – 95% have increased
levels

52. Other tests:
Absence ofA
TM protein on western
blot
Abnormal DNAsequence (mutation)
ofA
TM gene
Increased chromosomal breakage after
exposure of blood cells to X rays
Increased CA125

53. DI GEORGE SYNDROME
Defect : microdeletion in 22q11.2
So aka : 22q11.2 syndrome
Aka : velocardiofacial syndrome, conotruncal
anomaly face syndrome
MC microdeletion syndrome
2 imp gland abnormality

54. • Thymic hypoplasia
• T-cell number and
maturation defect
• So, increased
susceptibility to
infections
THYMUS
GLAND
• Underdeveloped and
hypoparathyroidism
occurs
• Hypocacemia occurs
PARATHYR
OID GLAND

56. FISH analysis toidentify 22q11.2 deletion
DIAGNOSIS