1. IMMUNODEFICIENCY DISEASES
For MBBS ( )
By: Dr. Puneet Kumar Gupta
Assistant Professor, Microbiology,

2. Introduction
Immunodeficiency diseases
Defence mechanisms of body are impaired→ repeated microbial infections
specific immune functions- humoral / cell- mediated immunity / both
Non-specific mechanisms such as phagocytosis & complement.

3. Introduction
Primary or Secondary 10 : abnormalities in development of immune mechanisms 20 : Consequences of disease, drugs, nutritional inadequacies & other processes interfere with proper functioning of mature immune system

4. Primary immunodeficiency diseases
Inducement: heredity,developmental defect Age: infancy and childhood Pathogenesis: differentiation & development of hemopoietic stem cells 1. IDD characterized by humoral immunity deficiency 2. IDD characterized by cellular immunity deficiency 3. Combined immunodeficiency diseases 4. Nonspecific immunodeficiency diseases

5. Phagocyte function

6. Common features of primary immunodeficiency diseases
Most of these diseases are inherited recessive disorders many are X-linked (M>F)
Recurrent or over-whelming infections in early childhood
Abnormality of acquired immunity
Innate immunity deficiencies are rare.

7. Common features of primary immunodeficiency diseases
Diseases resulting from developmental abnormality at initial stage of haemopoietic development, have more severe immunodeficiency usually of both innate & acquired immunity
Defects occurring at later stages usually lead to more specific deficiency of cellular or humoral variety

8. Humoral immunodeficiencies ( B cell defect )
X-linked agammaglobulinemia
Transient hypogammaglobulinemia of infancy
Common variable immunodeficiency
Selective immunoglobulin deficiencies
Immunodeficiencies with hyper-IgM
Transcobalamin II deficiency

9. Cellular immunodeficiencies ( T cell defect )
Thymic Hypoplasia ( DiGeorge syndrome )
Chronic mucocutaneous candidiasis
Purine nucleoside phosphorylase ( PNP ) deficiency
Biotin dependent multiple cocarboxylase deficiency
N K cell deficiency
Idiopathic CD 4 lymphopenia

10. III. Combined immunodeficiencies ( B & T cell defects):
Cellular immunodeficiency with abnormal immunoglobulin synthesis ( Nezelof syndrome )
b.Ataxia telangiectasia
c. Wiskott-Aldrich syndrome
d.Immunodeficiency with thymoma ( Good’s syndrome )
e. Immunodeficiency with short-limbed dwarfism / cartilage hair hypoplasia
f. Episodic lymphopenia with lymphocytotoxin
g.Severe combined immunodeficiencies
h. Omenn syndrome i. Bare lymphocyte syndrome j. Duncan’s syndrome
k. Reticular dysgenesis l. Nijmegen breakage syndrome m. GVHD

11. B. Disorders of non-specific immunity :
Disorders of phagocytosis: Disorders of complement :
Chronic granulomatous disease a. Complement component deficiencies
Myeloperoxidase deficiency b. Complement inhibitor deficiencies
Chediak-Higashi syndrome
Leucocyte G6PD defeciency
Job’s syndrome
Tuftsin deficiency
Lazy leucocyte syndrome
Hyper-IgE syndrome
Actin binding protein deficiency
Shwachman’s disease

12. I. IDD characterized by humoral immunity deficiency
B cell defects ( 50-60% )
It causes deficiency of Ig and antibody
Features： increased susceptibility to bacteria, enterovirus,
intestine parasites，delayed in growth and development
increased incidence of autoimmune diseases, malignant tumor
reduced numbers of peripheral blood B cells，absent or reduced
levels of Ig.
Pathogenesis: Block of differentiation & development of B cells,
reduced function of Th cells

13. X-LINKED AGAMMAGLOBULINEMIA
Described by Bruton ( 1952 )
1st immunodeficiency disease recognised.
Genetic features: x-linked recessive inheritance, males.
Pathogenesis: block in differentiation & development of
the pre-B cells.
Incidence : 1: 100,000 (UK)
Recurrent serious infections with pyogenic bacteria, pneumococci, streptococci, meningococci, Pseudomonas & H influenzae.
Live microbial vaccines should not be given to children.
Immunological features: Results in an absence or severe reduction in B lymphocytes & Ig of all types.

14. The Btk gene Located on the X chromosome.
Gene consists of 19 exons over a length of DNA of 37 kilobases.
Function of the Btk gene product is related to BCR signalling.
Without Btk pre-B cells fail to develop into mature B cells.

15. Clinical Findings LITTLE BOYS WITH BIG INFECTIONS!
Symptoms appear at 6-9 months of age (after loss of maternal Ig) .
Sites of infection: mucous membranes, ear (otitis media), lungs (bronchitis/pneumonia), blood (sepsis), gut (Giardia, or enterovirus), skin, eyes, meningitis.
Also seen: joint problems, kidney
problems, neutropenia, malignancy
in older patients.

16. Tonsils & adenoids are atrophic.
LN biopsy : depletion of bursa dependent areas
Plasma cells & germinal centres absent even after antigenic stimulation—No Ab formation
Marked ↓ in proportion of B cells in circulation.
CMI not affected
Delayed hypersensitivity of tuberculin & contact dermatitis types
Allograft rejection is normal
Arthritis, hemolytic anaemia & atopic manifestations
No Wheal & flare response of atopic hypersensitivity

17. Little boys with big infections
6 to 9 months old

18. Patients with XLA repeatedly acquire infections with extracellular pyogenic organisms such as:
Pneumococus
Hemophilus
streptococus

19. Sinusitis
Pneumonia
Otitis Media

20. TREATMENT
Intravenous Immunoglobulin (IVIG):300mg/kg of bd wt in 3 doses followed by monthly inj of 100mg/kg.
Whole plasma infusion
Donors being tested for hepatitis & other transmissible infections.

21. Selective immunoglobulin deficiencies
1% of all patients with recurrent infection.
Isolated IgA deficiency:
MC in this group
incidence 0.2% in normal populations.
Immunological features:
Serum IgA<5mg/dl but normal IgM and IgG
Genetic features : IgA Deficiency and genetic factors: association with HLA-A2, B8 and DW3 or A1 and B8.

22. Pathogenesis: failure in terminal differentiation of B cells due to intrinsic B cell defect or abnormal T cell help (TGF-B,IL-5) or in B cell responses to these cytokines
C/F:
atopic disorders
Recurrent infections in respiratory tract, alimentary canal, urogenital tract. .

24. Immunodeficiency with hyper IgM
Immunological features： increased level of IgM ( 10 mg/ml )， decreased levels of other Ig Pathogenesis: absent of the T cell effector CD40L，CD40L ( CD154 ) can not bind to CD40 of B cells→do not stimulate B cells to undergo Ab class switching Genetic features：X-linked recessive inheritance，boy Clinical features：recurrent pyogenic infections & autoimmune processes such as thrombocytopenia , neutropenia, hemolytic anaemia & renal lesions. Sometimes seen in congenital rubella.

25. Serum levels of immunoglobulin in Hyper IgM syndrome
IgG↓
IgM ↑↑
IgA↓
IgE↓

26. Hyper IgM syndrome Defect in CD40 ligand T cell B cell Ig Class switch

27. TRANSIENT HYPOGAMMAGLOBULINEMIA
Abnormal delay in initiation of IgG synthesis in some infants.
Maternal IgG is slowly catabolised in newborn & reaches 200mg/100ml by 2nd month.
Delay in synthesis of its own IgG by this age, immunodeficiency occurs.
Infants of both sexes.
Recurrent otitis media & respiratory infections
Spontaneous recovery: months of age.
Some cases require treatment with gammaglobulin.

28. COMMON VARIABLE IMMUNODEFICIENCY
Late onset hypogammaglobulinemia: manifests by years of age
Immunological features : total Ig<300 mg/100ml
IgG< 250 mg/100ml
B cells present in normal numbers, but defective in their ability to differentiate into plasma cells & secrete Ig
Increased suppressor T cell & diminished helper T cell activity
Clinical features :recurrent pyogenic infections & increased autoimmune diseases. Malabsorption & Giardiasis are common.
Treatment : administration of gammaglobulin preparations I.M or I.V.

29. CVID has an almost equal sex distribution

30. CVID Normal lymphoid follicle Normal number of circulating B cell
Hypogammaglobulinemia

31. Transcobalamin II deficiency
Genetic features : autosomal recessive
Immunological features : depleted plasma cells, diminished immunoglobulin levels & impaired phagocytosis.
Clinical features : patients show metabolic effects of vitamin B12 deficiency including Megaloblastic anaemia & intestinal villous atrophy.
Treatment :Vitamin B12 – restore hematopoietic , gastrointestional & B cell functions, but not phagocytic activity.

32. B-Cell Deficiency Disorders
Clinical Features
Therapy
1- X-linked agammaglobu-
linemia (Bruton disease)
Recurrent pyogenic infections; infections of lungs, sinuses, middle ear, skin, central nervous system
Immune serum globulin; antibiotics
2-Transient hypogamma-
globulinemia of infancy (1st 3 years of life)
Recurrent pyogenic infections; frequent in families with other immunodefi­ciencies
Antibiotics; immune serum globulin (selected patients)
3-Selective immuno-
globulin deficiency
(IgA, IgM, IgG sub­ classes)
Recurrent infections of lungs, sinuses; gastrointestinal disease; allergy; frequent in families with common variable immunodeficiencies
Antibiotics; immune serum globulin (IgG subclass defi­ciencies only)
4-Immunoglobulin defi­ciency with increased IgM (and IgD)
Infections of lungs, sinuses, middle ear; increased frequency of autoimmune disease Ectodermal displasea
Immune serum globulin; antibiotics
5-Common variable
immunodeficiency
Infections of lungs, sinuses, middle ear; giardiasis; malabsorption; autoimmune disease 32

33. II. IDD characterized by cellular immunity deficiency
T cell defects ( 5-10% ).
also Ig deficiencies because B and T cell immune systems are interdependent and cytotoxic disorders as well.
Features
increased susceptibility to intracellular microbes
Delay in growth and development
death in the early age
increased incidence of malignant tumor
reduced numbers of peripheral blood B cells，no reaction to DTH ，no reaction to HVG
block in the differentiation and development of the T cells

34. DiGeorge/Arch Syndrome
Developmental defect 3rd & 4th pharyngeal pouches
Aplasia or hypoplasia of thymus & parathyroid glands.
Probably due to some intrauterine infection or other complications.
gene deletions in DiGeorge chromosomal region at 22q11 & mutations in other unknown genes
M=F
DiGeorge syndrome may be partial (some T-cell function exists) or complete (T-cell function is absent).

35. Facial Defects: Infants low-set ears, fish shaped mouth, midline facial clefts, a small receding mandible ( micrognathia) , hypertelorism, a shortened philtrum, notched ear pinnae, antimongoloid slant
congenital heart disorder
Thymic and parathyroid hypoplasia or aplasia, causing T-cell deficiency and hypoparathyroidism.
Recurrent infections begin soon after birth, but the degree of immunodeficiency varies considerably, and T-cell function may improve spontaneously.
Hypocalcemic tetany appears within 24 to 48 h of birth.

36. usually associated with Fallot’s tetrology .
Frequent presenting sign occurs within first 24 hrs of life.
Patients who survive the neonatal period show enhanced susceptibility to viral, fungal & bacterial infections, which ultimately prove fatal.
Thymus-dependent areas of LN & spleen are depleted of lymphocytes. Circulating T cells are reduced in number.
Immunological features : Primarily involves CMI
humoral immune mechanismis largely unaffected.
Delayed hypersensitivity & graft rejection are depressed. Antibody response to primary antigenic stimuli is normal but secondary response to many antigens is impaired.

37. Chronic mucocutaneous candidiasis :
Abnormal immunological response to Candida albicans
C/F: Severe chronic candidiasis of mucosa, skin & nails.
Don’t show increased susceptibility to other infections but often have endocrinopathies
CMI to candida is deficient.
Delayed hypersensitivity to candida antigens is absent but circulating Ab to them are found in high titres.
Intracellular killing of candida is defective.
Treatment : Transfer factor therapy along with amphotericin B.

38. Purine nucleoside phosphorylase ( PNP) deficiency
Enz PNP is involved in the sequential degradation of purines to hypoxanthine & finally uric acid
Genetic features : autosomal recessive inheritance.
Immunological features : decreased CMI .
C/F: Recurrent or chronic infection
usually present with hypoplastic anaemia & recurrent pneumonia, diarrhea & candidiasis
Diagnosis : A low serum uric acid

39. 3、 Combined immunodeficiency diseases ( 20% ) :
1）SCID: severe combined immunodeficiency disease
2） immunodeficiency diseases with enzymes defect
3） immunodeficiency diseases with other severe defects

40. Severe combined immunodeficiencies (SCID)
Combined deficiency of humoral & cellular immunity .
Usually autosomal recessive disorder,
X-linked form (M>F) called primary lymphopenic immunologic deficiency
IL-2Rγ-chain defect is MC that leads to defective signalling by the IL-2, IL-4, IL-7, IL-9 & IL-15.
Variety of SCID characterised by CD 8+ T cells deficiency. It involves a tyrosine kinase- ZAP- 70.Consequently the T cell signalling is defective.

41. Severe combined immunodeficiencies (SCID)
Deficiency of recombinases RAG-1 & 2 – as they required for gene rearrangement, both T & B cells are affected.
Immunological features : decreased number of lymphocytes, thymus is either not developed or very poorly developed, small number of T cells fail to respond to antigens & experimental mitogens.

43. KNOWN CAUSES OF SCID Defect Impaired function Chromosomal location
IL-2Rγ
Signalling defect by IL-2,4,7,9 & 15
11p13
ADA deficiency
Toxic metabolite in T & B cells
20q13 & 14q13
PNP deficiency
JAK-3 deficiency
Defective signal from IL-2,4,7,9 & 15
19q13
ZAP-70 deficiency
Defective signal from TCR
2q12

44. Common Features of Severe Combined Immunodeficiency (SCID)
Failure to thrive
Onset of infections in the neonatal period
Opportunistic infections
Chronic or recurrent thrush
Chronic rashes
Chronic or recurrent diarrhea
Paucity of lymphoid tissue
Immunity is so low that even the live attenuated vaccines are not tolerated- they can produce diseases.
However patient’s life can be prolonged by confinement into a sterile environment.
Treatment : gene therapy.

46. Wiscott-aldrich syndrome
X-linked immunodeficiency which increases with age.
Genetic features :defective CD43 protein gene on short arm of X chromosome ( Xp11 ).
This gene encodes a glycoprotein called sialophorin (expressed on lymphoid cell, neutrophils, macrophages & platelets)
Immunological features : CMI undergoes progressive deterioration associated with cellular depletion of thymus & paracortical areas of lymphnodes.

47. IgG & IgA levels are normal or elevated
Serum IgM level is low
IgG & IgA levels are normal or elevated
humoral defect appears to be specific inability to respond to polysaccharide antigens.
C/F: eczema, thrombocytopenic purpura & recurrent infections.
Affected boys rarely survive the first decade of life, death being due to infection, hemorrhage or lymphoreticular malignancy.
Treatment : BMT & transfer factor therapy.

48. ATAXIA-TELANGIECTASIA
Hereditary condition transmitted in the autosomal recessive mode, where combined immunodeficiency is associated with cerebellar ataxia, telangiectasia, ovarian dysgenesis & chromosomal abnormalities.
Genetic features : Gene responsible on chromosome 11
Gene product may play a role in DNA repair
ATM gene encodes Atm protein kinase, a member of phosphatidyl inositol 3-kinase family
Clinical features : earliest signs- ataxia & chorioathetoid movements noticed in infancy. Telangiectasia involving the conjuctiva & face appears at 5 or 6 years of age.

49. Disease is progressive, with both neurological defects & immunodeficiency becoming severe with time.
Death occurs due to sinopulmonary infection early in life , or malignancy in 2nd or 3rd decade.
Immunological features :
ID may affect T&B cells
IgA, IgE and IgG2 deficiency.
T cell function is variably depressed.
CMI is also defective resulting in impairment of delayed hypersensitivity & graft rejection.
Treatment : Transfer factor therapy & fetal thymus transplants.

50. Cellular immunodeficiency with abnormal immunoglobulin synthesis ( Nezelof syndrome ) :
Group of disorders, probably of varied origin
depressed CMI is associated with selectively elevated, decreased or normal levels of immunoglobulin
Clinical features : recurrent fungal, bacterial, viral & protozoal diseases associated with hemolytic anaemia commonly.

51. Treatment : BMT, transfer factor & thymus transplantation.
Cellular immunodeficiency with abnormal immunoglobulin synthesis ( Nezelof syndrome ) :
Immunological features : marked deficiency of T cell immunity & varying degrees of deficiency of B cell immunity .
Thymic dysplasia occurs with lymphoid depletion.
Abundant plasma cells (spleen, LN, intestines & elsewhere in body)
Inspite of normal levels of immunoglobulins, antigenic stimuli don’t induce antibody formation.
Treatment : BMT, transfer factor & thymus transplantation.

52. Phagocytic cell defects (10 to 15%)
The ability of phagocytic cells (eg, monocytes, macrophages, granulocytes such as neutrophils and eosinophils) to kill pathogens is impaired. Cutaneous staphylococcal and gram-negative infections are characteristic. The most common phagocytic cell defects are chronic granulomatous disease, leukocyte adhesion deficiency, and Chédiak-Higashi syndrome

53. Chronic granulomatous disease
Defect in generation of oxidative radicals needed by the host phagocytic cells to kill the bacteria & other pathogens. Genetic features : Mutation in NADPH .X-linked congenital defect -70%, autosomal recessive form – 30%.Decreased hydrogen peroxide production due defective NADPH oxidase. Immunological features : Besides free radical generation deficiency, there are also defects in mononuclear cells to function as APCs. Both antigen processing & presentation are affected leading to inadequate T cell activation. Humoral & cellular immune response are normal.

55. Clinical features : recurrent infection with low grade pathogens, starting early in life progress & outcome fatal Chronic suppurative granulomatous lesions develop in skin & lymph nodes, along with hepatosplenomegaly, progressive infiltration of lungs & granulomatous septic osteomyelitis. Diagnosis : NBT ( Nitroblue tetrazolium )test : leucocytes from patients fail to reduce nitoblue tetrazolium during phagocytosis. Treatment : Interferon gamma .

56. Chest X-ray in cgd

57. CGD patient with
skin infections
due to Serratia
marcescens

58. Secondary immunodeficiency disorders
category
Endocrine GI
Hematologic
Iatrogenic
Infectious
Examples
Diabetes mellitus
Hepatic insufficiency, hepatitis, intestinal lymphangiectasia, protein-losing enteropathy
Aplatic anemia, cancer, graft-vs-host disease, sickle cell disease
Certain drugs: chemotherapeutic drugs, immunosuppressants, corticosteroids, radiation therapy; splenectomy
Cytomegalovirus, Epstein-Barr virus, HIV, measles virus, varicella-zoster virus

59. Continued…. Nutritional Physiologic Renal Rheumatologic Other
Alcoholism, undernutrition
Physiologic immunodeficiency in infants due to immaturity of immune system, pregnancy
Nephrotic syndrome, renal insufficiency, uremia
RA, SLE
Burns, chromosomal abnormalities (eg, Down syndrome), congenital asplenia, critical and chronic illness, histiocytosis, sarcoidosis

60. REFERENCES Textbook of Microbiology – Ananthanaryanan & Paniker’s
Roitt’s Immunology
Kuby immunology

61. Thank you