Immunodeficiency

Francis Ian L. Salaver, RMT Aileen Grace L. Ang, RMT, MAST-Bio

Definition

A group of disorders characterized by an impaired ability to produce normal immune response. Most of these disorders are caused by mutations in genes involved in the development and function of immune organs, cells, and molecules.

Origins of Immunodeficiency
Primary or Congenital
Inherited genetic defects in immune cell development or function, or inherited deficiency in a particular immune molecule

Secondary or acquired
A loss of previously functional immunity due to infection, toxicity, radiation, splenectomy, aging, malnutrition, etc.

Types of immunodeficiency disorders:

1- Primary: Causes in immune system component:
a. According of component:

i.
ii. iii.

Complements.
Phagocytic. B cells.

iv.

T Cells.

b. According to the etiology: i. ii. iii. iv. Congenital (X-linked disease) Acquired (AIDS) Embryogenesis (DiGeorge syndrome). Idiopathic
4

Types of immunodeficiency disorders:

2- Secondary: Non Immunogenic causes:
a. b. c. d. e. Prematurity Mal nutrition. Hodgkin`s and others malignancy. Injury, Burns, Splenectomy. Drugs.

Antibody deficiencies include: Common variable immunodeficiency (CVID) X-linked agammaglobulinemia (XLA) Selective IgA deficiency (SIgAd) Selective IgG subclass deficiency (SIgGsd) Hyper IgM syndrome (HIgM) Transient hypogammaglobulinemia of Infancy (THI)

Cellular deficiencies include:

Severe combined immunodeficiency (SCID) Ataxia-Telangiectasia syndrome (AT) Wiskott-Aldrich syndrome (WAS) DiGeorge syndrome Chronic mucocutaneous candidiasis (CMCC)

Phagocytic disorders include: Chronic granulomatous disease (CGD) Leukocyte adhesion defect (LAD) Chediak-Higashi syndrome (CHS) Swhachman syndrome (Swh.S) Hyper IgE syndrome (Job syndrome) Complement deficiencies

Infectious Consequences of Immunodeficiency

Antibody deficiency, Phagocyte deficiencies, or Complement protein deficiencies are associated with recurrent infections with extracellular pyogenic bacteria (pneumonia, otitis media, skin infections)
Deficiency in Cell-mediated immunity is associated with recurrent or chronic viral, fungal, or protozoal diseases.

Infectious Consequences of Immunodeficiency

T-cell problems often also result in B-cell problems, due to T-dependent Ags. Both, or all- bacterial, viral, problems with commensals, etc. Patients with immunodeficiency are also susceptible to certain types of cancer

Type of the infecting organism

Recurrent viral, fungal, mycobacterial, or opportunistic infections suggest T-cell defects.
Recurrent infections with invasive encapsulated bacteria (e.g: pneumococcus) suggest B-cell defects. Recurrent infections with bacteria of low virulence (e.g: staph) suggest a neutrophil abnormality. Recurrent Neisseria infections suggest terminal complement defect.

Primary Immunodeficiency: Frequency

Phagocytic 18% Cellular 10% Combined 20% Complement 2%

Antibody 50%

The overall prevalence of PID is about 1:2000

Development of Immune cell

THYRUM Epi. CD3+

CD4+ CD8+

TH1 IFN-IL-2

BM
SC SL
ProB CFU

PT

T
CD19+ CD20 +

PreB

TH2 IL-4 5 CTL 8910 13 IgM IgM Plasma IgG B

Plasma

IgG IgA IgE

IgA
RBC

Plet PMN

B
B

Plasma

IgE
Plasma

B cell Deficiencies
X-linked Agammaglobulinemia
B cell defect
Defect in kinase that keeps B cells in pre-B stage with H chains rearranged but L chains not

Low levels of IgG and absence of other classes Recurrent bacterial infections Symptoms at 9 mo. to 2 yr of age Treat with intravenous immunoglobulin (IVIG)

X-linked Agammaglobulinemia
It is failure of B-cells to mature beyond the pre-B cell stage in the bone marrow Failure is caused by mutations or deletions in the gene encoding an enzyme called B-cell tyrosine kinase (Btk) Btk is involved in transducing signals from the pre- B cell receptor required for continued maturation of the cells

Molecular Defects in Lymphocyte Maturation

Bruton disease mutations in btk

maturation disorder of pre-B cell

Immunoglobulin Levels vs. Age

Antibody Deficiencies X-Linked Agammaglobulinemia

Age of onset of symptoms
4-12 months of age

Inheritance Pathogenesis

X-linked
Mutations in the gene for Btk arrest in devt of B cells (pre-B stage) decreased number of circulating B cells and absent or very low levels of all Ig classes
Well during the 1st 6-9 months of life because of maternally transmitted IgG antibodies. Chronic or recurrent pyogenic bacterial sinopulmonary or gastrointestinal infections;

Symptoms

B cell Deficiencies
Common Variable Immunodeficiency
is a disorder that involves the following: (1) low levels of most or all of the immunoglobulin (Ig) classes, (2) a lack of B lymphocytes or plasma cells that are capable of producing antibodies, and (3) frequent bacterial infections.

B cell Deficiencies
Common Variable Immunodeficiency
One study showed that, when B lymphocytes were stimulated with pokeweed mitogen in vitro, plasma cells failed to differentiate, even in the presence of normal T cells. This finding suggests a defect in B-cell expression in surface molecules.

B cell Deficiencies
Transient hypogammaglobulinemia of infancy
Primarily due to delayed maturation of T cells As the child ages, the number and condition of Thelper cells improves and this situation corrects itself. Hypogammaglobulinemia is characterized by low levels of gammaglobulin (antibodies) in the blood.

B cell Deficiencies
X-linked Hyper-IgM Syndrome
Deficiency of IgG, IgE, IgA but elevated levels of IgM Defect in T cell surface marker CD40L
This is needed for interaction between TH and B cell for class switching for T-dependent antigens T independent antigens???

Molecular Defects In Lymphocyte Activation and Function

Antibody Deficiencies Hyper-IgM Syndrome

Age of onset of symptoms Inheritance Pathogenesis
1-2 years of age Genetically heterogenous Mutation in the gene for CD154(40L) on T cells, which is the ligand for CD40 on B cells inability to signal B cells to undergo isotype switching B cells produce only IgM. X-linked Hyper IgM: small tonsils, no palpable lymph nodes; recurrent pyogenic infections

Clinical Manifestations

B cell Deficiencies
Hyper-IgE Syndrome (Job syndrome)
Autosomal dominant Skin abscesses, pneumonia, eczema, facial abnormalities High # of eosinophils and IgE

B cell Deficiencies
Hyper-IgE Syndrome (Job syndrome)
Imbalance of TH 1 and TH 2 responses, decreased production/expression of interferon (IFN)- Elevated production/expression of interleukin (IL)-4 Defects in IFN- and IL-12 pathways, underexpression of certain chemokines and adhesion molecules Reduced expression of transforming growth factor (TGF-) and IFN- messenger RNA (mRNA) in circulating activated T cells

B cell Deficiencies
Selective Deficiences of Immunoglobulin Classes
IgA deficiency is most common
Can be caused by problems in class switching, deletion of IgA mRNA during processing, Recurrent respiratory and urinary tract infections, intestinal problems Associated with autoimmune disorders and allergic reaction

B cell Deficiencies
Selective Deficiences of Immunoglobulin Classes
IgA deficiency is most common
Associated with one type of transfusion reaction
Selective IgA deficiency is an inherited disease, resulting from a failure of B-cells to switch from making IgM, the early antibody, to IgA. Although the B-cell numbers are normal, and the B-cells are otherwise normal (they can still make all other classes of antibodies), the amount of IgA produced is limited. This results in more infections of mucosal surfaces, such as the nose, throat, lungs, and intestines.

B cell Deficiencies
Selective Deficiences of Immunoglobulin Classes
IgG deficiencies are rare
Selective IgG subclass deficiencies is a group of genetic diseases in which some of the subclasses of IgG are not made. There are four subclasses in the IgG class of antibodies. As the B-cell matures, it can switch from one subclass to another. In these diseases there is a defect in the maturation of the Bcells that results in a lack of switching.

Immunoglobulin levels in adults IgA 80-350 mg/dL IgG 620-1400 mg/dL IgM 45-250 mg/dL IgD O.3-3 mg/dL IgE 0.02 0.2 mg/dL

Reference range for serum immunoglobins based on age

Age 0-1 mo 1-4 mo 4-7 mo 7-13 mo 13-36 mo 3-6 yr 6 yr-adult IgG (mg/dL)
700-1300 280-750 200-1200 300-1500 400-1300 600-1500 639-1344

IgA (mg/dL)
0-11 6-50 8-90 16-100 20-230 50-150 70-312

IgM (mg/dL)
5-30 15-70 10-90 25-115 30-120 22-100 56-352

From the laboratories of Childrens Hospital, Boston, Mass.

T Cell Deficiencies
Pure T Cell Deficiencies:
DiGeorge syndrome T cell receptor deficiencies Zap 70 deficiency

DiGeorge Syndrome
Conotruncal cardiac malformation Hypoparathyroidism Thymic hypoplasia leading to variable immunodeficiency The result of common 22q11.2 deletion is a developmental field defect involving the third and fourth pharyngeal pouches leading to defective migration of the neural crest cells during the fourth week of embryogenesis. Portions of the heart, head and neck, thymus, and parathyroids derive from these pouches. Other features:
Characteristic facies Deletion in 22q11 in > 80% Affected gene(s) is a transcription factor in the T-box family called Tbx1

Velo-cardio-facial syndrome

Thymus
DiGeorge Syndrome decreased or absent thymus
Results from deletion of region on chromosome 22 in developing embryo, developmental anomaly Lowered T cell numbers, results in B cells not producing sufficient Abs

Cardiac defects Abnormal facies Thymic hypoplasia Cleft palate Hypocalcaemia resulting from 22q11 deletions.

Primary Immunodeficiency of B and T cells

Severe Combined Immunodeficiency

X-linked SCID: Swiss-Type SCID Bare Lymphocyte syndrome Purine nucleoside phosphorylase deficiency Omenn syndrome

Severe Combined Immunodeficiency

Bare Lymphocyte syndrome
Rare recessive genetic condition in which a group of genes called major histocompatibility complex class II (MHC class II) are not expressed. Problems with activators of MHC Class II gene transcription (transcription factor RFX (RFX-B, RFX5, and RFXAP) and the class II transactivator CIITA)

Severe Combined Immunodeficiency

X-linked SCID:
X-linked recessive trait, stemming from a mutated (abnormal) version of the IL2-receptor gene located at xq13.1 on the X-chromosome, which is shared between receptors for IL-2, IL4, and IL-7. Body produces very little T cells and NK cells

Severe Combined Immunodeficiency

Swiss-Type SCID
Adenosine deaminase deficiency Autosomal recessive ADA deficiency is due to a lack of the enzyme adenosine deaminase. This deficiency results in an accumulation of deoxyadenosine

Severe Combined Immunodeficiency

Swiss-Type SCID
a build up of dATP in all cells, which inhibits ribonucleotide reductase and prevents DNA synthesis, so cells are unable to divide. Since developing T cells and B cells are some of the most mitotically active cells, they are highly susceptible to this condition. an increase in S-adenosylhomocysteine since the enzyme adenosine deaminase is important in the purine salvage pathway; both substances are toxic to immature lymphocytes, which thus fail to mature.

ADA PNP deficiency

deaminization
inosine

ADA deficiency

deoxyadenosine

dAMP
dADP dATP

blood Uric acid urine

DNA synthsize

ribonucleotide reductase

T/B cell mature compromised

dGTP
dGDP

uridine

PNP deficiency

deoxyguanosine

dGMP

Severe Combined Immunodeficiency

Purine nucleoside phosphorylase deficiency
Autosomal recessive Impairment of this enzyme causes elevated dGTP levels resulting in T-cell toxicity and deficiency In contrast to adenosine deaminase deficiency (another deficiency of purine metabolism), there is minimal disruption to B cells.

Severe Combined Immunodeficiency

Omenn syndrome
Autosomal recessive Associated with mutations in the recombination activating genes (RAG1 and RAG2), affecting circulating levels of both B-cells and T-cells

Severe Combined Immunodeficiency

Artermis/DCLRE1C
Protein that in humans is encoded by the DCLRE1C (DNA cross-link repair 1C) gene Without the gene, children's bodies are unable to repair DNA This gene encodes a nuclear protein that is involved in V(D)J recombination and DNA repair

Severe Combined Immunodeficiency

Artermis/DCLRE1C
Protein that in humans is encoded by the DCLRE1C (DNA cross-link repair 1C) gene Without the gene, children's bodies are unable to repair DNA This gene encodes a nuclear protein that is involved in V(D)J recombination and DNA repair

Severe Combined Immunodeficiency

Reticular Dysgenesis
Caused by mutations in the AK2 gene (1p34). The resulting deficiency in adenylate kinase 2 causes increased apoptosis of myeloid and lymphoid precursors.

Severe Combined Immunodeficiency

JAK 3 deficiency

Wiskott-Aldrich Syndrome
X-linked recessive disease characterized by eczema, thrombocytopenia and immune deficiency Defect in the WASP gene WAS gene mutations impair WASP's role in cell signaling and disrupt the function of the actin cytoskeleton in certain immune cells and blood cells. Immune cells that lack WASP function tend to have trouble responding to factors that trigger cell growth and division (proliferation).

Ataxia-telangiectasia
Caused by a defect in the ATM gene,which is responsible for managing the cells response to multiple forms of stress including double-strand breaks in DNA. (autosomal recessive)
In simple terms, the protein produced by the ATM gene recognizes that there is a break in DNA, recruits other proteins to fix the break, and stops the cell from making new DNA until the repair is complete.

Ataxia-telangiectasia
Mutations in the ATM gene reduce or eliminate the function of the ATM protein. Without this protein, cells become unstable and die. Cells in the part of the brain involved in coordinating movements (the cerebellum) are particularly affected by loss of the ATM protein.
The loss of these brain cells causes some of the movement problems characteristic of ataxia-telangiectasia.

Ataxia

Phagocyte Deficiencies
Chronic Granulomatous Disease
NADPH oxidase defect

Chediak -Higashi Syndrome

Abnormal lysosome formation

Leukocyte Adhesion Deficiency

Absence of leukocyte adhesion molecules

Phagocyte Deficiencies
Chronic Granulomatous Disease
NADPH oxidase defect An inherited disorder of phagocytic cells, results from an inability of phagocytes to produce bactericidal superoxide anions (O2-).

Chronic granulomatous disease

Normsal phagocyte Dysfunction of phagocyte

Neutrophil
Bacteria phagosome
NADPH H+

Bacteria Phagosome
NADPH H+

e- +O2
O2H2O2 H+

Nitroblue tetrazolium test

The panel on the right demonstrates that neutrophils ingest the dye, nitroblue tetrazolium, and in the presence of reactive oxygen species, the yellow colored NBT compound is converted to the purple-blue formazan compound.

Dihydrorhodamine Flow Cytometry based assay

This test is based on the principle that nonfluorescent DHR (dihydrorhodamine) 123 when phagocytosed by normal activated neutrophils (after stimulation with PMA phorbol myristate acetate) can be oxidized by hydrogen peroxide, produced during the activated neutrophil respiratory oxidative burst, to rhodamine 123, a green fluorescent compound, which can be detected by flow cytometry.

Phagocyte Deficiencies
Chediak -Higashi Syndrome
Abnormal lysosome formation Autosomal recessive disorder that arises from a microtubule polymerization defect which leads to a decrease in phagocytosis. Caused by mutations in the LYST gene which provides instructions for making a protein known as the lysosomal trafficking regulator. Researchers believe that this protein plays a role in the fusion of phagosome and lysosome

Phagocyte Deficiencies
Chediak -Higashi Syndrome
Also involves problem with skin pigmentation albinism

Phagocyte Deficiencies
Leukocyte Adhesion Deficiency
Absence of leukocyte adhesion molecules Results from an impaired step in the inflammatory process, namely, the migration of leukocytes from the blood vessels to sites of infection, which requires adhesion of leukocytes to the endothelium.

Phagocyte Deficiencies
Leukocyte Adhesion Deficiency
LAD-I is caused by mutations in the ITGB2 gene (21q22.3), encoding the beta-2-integrin CD18. LAD-II results from mutations in the SLC35C1 gene (11p11.2), encoding the guanosine 5'diphosphate (GDP)-fucose transporter.

Complement Deficiencies
Single component deficiencies
Example: C3 deficiency

Hereditary Angioedema
C1 Inhibitor deficiency

C5,C6,C7,C8, or C9 deficiency
Recurrent bacterial meningitis due defective membrane attack complex

Causes of Acquired Immunodeficiency

Cancer (immunoproliferative diseases) Cytotoxic drugs or radiation Malnutrition Splenectomy Immunosuppressive therapies Stress/emotions Aging (thymic atrophy) Infection

Immunodeficiency Syndromes

Immunodeficiency Syndromes

Immunodeficiency Syndromes