Immunodeficiency Diseases March 2014 (1)

Immunodeficiency Diseases

Bharati B

Learning objectives• List the immunodeficiency diseases resulting from defects in

phagocytic cells, B cells, T cells, T cells and B cells combined and complement

• Describe the molecular defects of each of the immunodeficiency diseases

• Recognize the infections most likely to be seen in each of immunodeficiency diseases

• Recognize/ identify a immunodeficiency disease from the signs and symptoms associated with the defect and the specific molecular defect

Immunodeficiency

• Failure of the immune system to protect against disease or malignancy • Result of a genetically incompetent or deregulated immune system

• May result from abnormalities of:• Phagocytes, Complement, B cells, production of antibodies, and T cells

due to defects in their maturation, activation or deficiency

• May be recognized because of:• Increase in incidence of infections• Increase in severity of infections• Unusual etiology of infection (opportunistic infections)• Dysfunction/ abnormality of cells or organs not directly related to the

immune system

Immunodeficiency

• Primary Immunodeficiency• Congenital immune deficiencies or

developmental defects in immune system

• These defects are present at birth but may show up later on in life

• Generally present with:– Recurrent ear infections/yr– Sinus infections, pneumonias,

meningitis, or sepsis/yr– Recurrent abscesses– Persistent thrush

• Secondary immunodeficiency• Loss of immune function that develops

later in life as a direct consequence of some other recognized cause

• Acquired immune deficiencies that arise from:– Medical intervention (iatrogenic)– Antirejection drugs post transplant– Immunomodulating drugs for

autoimmune conditions– Chemotherapy & radiation for

malignancy– Infections/ cancers/Myeloma, leukemia– HIV/AIDS, other viruses– Metabolic/ toxic– Diabetes, renal & hepatic failure Aging

• 2 general types: Primary (Congenital) & Secondary (Acquired)

General Features of Immunodeficiency diseases

• Principal consequence of immunodeficiency is an increased susceptibility to infections– Type of infection depends on the nature of immunodeficiency.– Defects in humoral immunity results in increased susceptibility

to infection with encapsulated, pus forming bacteria and some viruses

– Defects in cell mediated immunity lead to infection with viruses and intracellular microbes

• Increased susceptibility to certain types of cancer• Increased incidence of autoimmunity• Immunodeficiency may result from defects in lymphocyte

development or activation or from defects in the effector mechanisms of innate and adaptive immunity

Features of Immunodeficiency affecting T or B lymphocytes, phagocytes

Type of pathogen T-cell defect B-cell defect Granulocyte

defect Complement defect

Bacteria Bacterial sepsis Streptococci, Staphylococci, Haemophilus

Staphylococci, Pseudomonas

Neisserial infections, other pyogenic bacterial infections

Viruses CMV, EBV, severe VZV, chronic infections with respiratory & intestinal viruses

Enteroviral encephalitis

Fungi & parasites

Candida, Pneumocystis jiroveci

Severe intestinal giardiasis

Candida, Nocardia, Aspergillus

Special features

Aggressive disease with opportunistic pathogens, failure to clear infections

Recurrent sinopulmonary infections, sepsis, chronic meningitis

Examples of Infections in Immunodeficiency

Congenital Disorders of Innate Immunity

• Defective production of reactive oxygen species by phagocytes resulting in recurrent catalase positive bacterial & fungal infections

• Recurrent infections with cat+ • Staphylococcus aureus• Pseudomonas species• Serratia species• Klebsiella species• Candida species

Chronic Granulomatous Disease (CGD)

• Neutrophils, Macrophages are affected

• Poor intracellular killing and low respiratory burst.

• In majority of these patients, the deficiency is due to:• A defect in NADPH oxidase that participate in phagocytic

respiratory burst• (Phagocytic oxidase enzyme complex) phox• Defective reactive oxygen species production

• Infections not controlled by phagocytes, so T-cell mediated activation is turned on

• Exhibit inflammatory reaction resulting in the formation of granulomas (macrophages, T cells)

• Characterized by marked lymphadenopathy, hepatosplenomegaly and chronic draining lymph nodes

• Autosomal recessive or X-linked trait

• Treatment with IFN-γ


• Respiratory Burst triggered in macrophages and neutrophils cause a transient increase in oxygen consumption during production of microbicidal oxygen metabolites which ultimately kill microbes through

• Reactive Oxygen species (ROS)• Nitric Oxide (NO)• Individuals who have defective NADPH

will not produce H2O2 (hydrogen peroxide)

• Bacteria produce some hydrogen peroxide which is used by myeloperoxidase

• Infections with catalase positive bacteria will destroy the hydrogen peroxide and therefore no substrate for myeloperoxidase

Mechanism of Respiratory Burst

Nitroblue tetrazolium test

• CGD patients can be diagnosed on the basis of poor Nitroblue tetrazolium (NBT) reduction which is a measure of respiratory burst

• negative reaction in the nitroblue tetrazolium test which in normal individual turns blue due to reduction by superoxide anions.

• Step1: neutrophils placed on slide with an activator to induce activation of NADPH

• Step 2: Drop of nitroblue tetrazolium (yellow color) added to the slide

• In the presence of normal NADPH the yellow dye turns purple (positive test)

• In the absence it remains yellow (negative test)

• Patients with CGD the test is negative (yellow)

NBT reduction

• Positive reaction in the nitroblue tetrazolium test normal cells turns blue due to reduction by superoxide anions.

• Negative reaction in the nitroblue tetrazolium test in which abnormal cells are yellow due to absence of superoxide anions.

• Myeloperoxidase deficiency: • Myeloperoxidase is green

contributes to the color of pus• Individuals with

myeloperoxidase deficiency can still kill bacteria but more slowly (no ClO- produced)

• Individuals with myelperoxidase deficiency will be susceptible to bacterial infections

• Will be positive by NBT test


• Inherited defect (autosomal recessive) in phagolysosome function:

• Affected gene encodes LYST protein that regulates lysosomal trafficking

• Defective fusion of phagosome-lysosome in phagocytes

• Reduced intracellular killing and chemotactic movement

• Defective degranulation• Delayed microbial killing• Neutropenia

• Giant lysosomes are often seen and fail to function (Granule structural defect).

• Extremely large granules are seen in the cytoplasm of granulocytes.

• Result from abnormal fusion of granules during their formation

• The respiratory burst is normal. • Resulting in recurrent infections

with pyogenic bacteria, especially in the skin & respiratory tract

Chédiak-Higashi Syndrome

Giant granules

A history of recurrent bacterial infections and giant granules seen in peripheral blood leukocytes is characteristic for Chediak-Higashi syndrome.

• Other cells affected by this disorder • Melanocytes (partial albinism)• Platelets (bleeding disorders)• Cells of the nervous system; Schwann cells

(neuropathy), • NK and cytotoxic T cells (aggressive

lymphoproliferative disorder).

Chédiak-Higashi Syndrome

• Job’s syndrome (hyper-IgE syndrome):

• TH1 cells can not make IFN-γ, which reduces the ability of macrophages to kill bacteria. This leads to an increase in TH2 cells and high level IgE level.

• Increased IgE causes histamine release, which blocks certain aspects of the inflammatory response and inhibits neutrophil chemotaxis

• Patient’s have recurrent cold staphylococcus abscesses, eczema, & high IgE

Other Phagocyte Deficiencies

Kaplan Medical USMLE step 1; Immunology and Microbiology lecture notes

22

Biological function of TH1 and TH2 subsets

TH1 TH2

Fig 31Fig 30.

• LFA-1: CD11a CD18• Mac-1: CD11b CD18

• LAD-1: Mutation in gene encoding common β chain (CD18) of a few integrins including LFA-1 and Mac-1 that mediate adhesion to endothelium and other cells

• Cells affected:• Neutrophils, lymphocytes,

monocyte/macrophages, NK cells• Functional defects: mostly

adhesion-dependent leukocyte functions are impaired

• Chemotaxis, diapedesis, adherence, phagocytosis, CTL & NK cytotoxicity

Leukocyte Adhesion Deficiency Syndrome (LAD-1)

• Associated features:• Delayed cord separation

(omphalitis), failure to form pus, chronic skin ulcers, periodontitis, leukocytosis, defective T & NK cytotoxicity

• Inheritance: Autosomal Recessive• Treatment is with bone marrow

(devoid of T cells and MHC-matched) transplantation or gene therapy.

Leukocyte Adhesion Deficiency Syndrome (LAD-1)

Defects in phagocytic cells are associated with persistence of bacterial infection

Disorders of Complement System

• C3b deficiency from insufficient C3 synthesis are particularly susceptible to sepsis with pyogenic bacteria that may be fatal

• Shows importance of C3b in opsonization & enhanced phagocytosis

• Immune complex disease; SLE• C5, C6, C7, or C8 deficiency are prone to Neisseria infections

• Defects in C’ components results in immunodeficiency• lead to increased susceptibility to bacterial infections.

Hereditary Angioedema

• Autosomal dominant disease • Results from deficiency in C1

inhibitor deficiency (C1-INH) which targets C1r, C1s, factor XII of the coagulation pathway, kallikrein pathway

• In the absence of INH• C1 continues to act on C4 to

generate C4a– C4a subsequently triggers

vasoactive components C3a, C5a

– Bradykinin release

• Lead to edema of skin and mucosal surface of respiratory and GIT following minor trauma or emotional stress– Larygeal edema can be fatal– Nausea ,vomiting, diarrhea

Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2012 by Saunders, an imprint of Elsevier Inc.

Regulation of C1 Activity by C1 INH

Fig. 12-13

Paroxysmal Nocturnal Hemoglobinuria (PNH)• Acquired , clonal, hematopoietic

stem cell disorder• Somatic mutation of PIG-A gene

(phosphatidyl inositol glycan class A gene) in a myeloid stem cell clone

• Codes for anchoring proteins GPI (glycosyl phosphatidylinositol) which anchors many proteins to cell membrane example– CD 55 (DAF) inhibitors of C– CD 59 (membrane inhibitor

of reactive lysis)– CD 14 (Macrophages)– CD 16 (NK cells)– C8 binding proteins

• Defect in anchoring of CD 55 and CD 59 on the surface of RBC, Neutrophils and platelets

• CD55 and CD 59 degrade C3 and C5 convertase thus preventing MAC deposition on normal cells and their lysis

• Intravascular complement mediated lysis of RBC, platelets and neutrophils

• Occurs at night because respiratory acidosis enhances complement attachment


Inhibition of C3 Convertase Formation

Fig. 12-14


Regulation of MAC Formation

Fig. 12-16

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Clinical Findings:• Iron deficiency due to episodic

hemoglobinuria (microcytic anemia)

• Increased vessel thrombosis (due to release of aggregating agents from platelets)

• Increaed risk of developing acute myeloblastic leukemia ( because of defect in stem cell

• Diagnosis: Flow cytometry for CD55 and CD 59

Defects of Humoral Immunity

B cell & Antibody Deficiencies

Sites of lymphocyte development block in some primary immunodeficiency diseases

ADA: adenosine deaminaseAID: activation-induced deaminase

Disease Functional Deficiencies Mechanism of DefectAgammaglobulinemiasX-linked Brutons Decrease in all serum Ig isotypes;

reduced B cell numbersPre-B receptor checkpoint defect; Btk mutation

Hypogammaglobulinemias/isotype defectsSelective IgA deficiency Decreased IgA; may be associated with

increased susceptibility to bacterial infections and protozoa such as Giardia lamblia

Failure to class switch

Selective IgG2 deficiency Increased susceptibility to bacterial infections

Small subset have deletion in IgH γ2 locus

Common variable immunodeficiency

Low IgG ; IgA, variable IgM ; normal or decreased B cell numbers

Hyper-IgM syndromes ( Combined B and T cell ) X-linked Defects in T helper cell-mediated B cell,

macrophage, and dendritic cell activation; defects in somatic mutation, class switching, and germinal center formation; defective cell-mediated immunity

Mutation in CD40L

B cell & Antibody deficiencies

X- Linked Agammaglobulinemia

• Disorder: Bruton’s agammaglobulinemia

• The most severe hypogammaglobulinemia

• Functional deficiencies: absence of antibody production, lack of B cells

• Mature B cells are absent as they exist in the pre-B cell stage with H, but not L, chains rearranged

• Patients have failure of B-cell maturation associated with a defective B cell tyrosine kinase gene (Btk)

• BTK: phosphorylating enzyme that Pre-B cells use to signal that they have successfully put the Pre-BCR on the B cell surface

• Result: patients have no Antibodies (all serum isotypes) and suffer severe & recurrent bacterial infections

• May have small amount of IgM

FIGURE 7.1. Stages in differentiation of B lymphocytes. Dashed lines on the pre-B cell indicate surrogate light chains. The two lines associated with the cell surface heavy chain represent the signaling molecules Ig and Ig (CD79a and b).

X-agammaglobulinemia – Ig Levels

Maternal IgG passivelyacquired

Figure 12.8. Immunoelectrophoresis

Diagnosis is based on enumeration of B cells & Antibody measurement

Immunoelectrophoresis reveals the absence of several distinct Abs in serum from XLA patient

Diagnosis is based on enumeration of B cells & Ab measurement

Flow cytometry shows loss of B Cells in XLA

Selective immunoglobulin deficiency (IgA)

• Hypogammaglobulinemias/ isotype defects:

• IgA deficiency is the most common of all primary immunodeficiencies known (1/700 of all Caucasians)

• Results from a defect in heavy chain class switching. Leads to Failure to mature into plasma cells, drop in secretory IgA.

• IgA-deficient patients are very susceptible to pyogenic bacterial infections (especially in sinus and lungs), gastrointestinal, eye and nasopharyngeal infections.

• Decrease in secretory and serum IgA

• Patients with IgA deficiency have a high incidence of autoimmune diseases (particularly immune complex type) and lymphoid malignancies.

• Anaphylaxis on exposure to blood products with IgA

• Laboratory diagnosis is based on IgA measurement.

Transient hypogammaglobulinemia

• Children, at birth, have IgG levels comparable to that of the mother.

• Because the half life of IgG is about 30 days, its level gradually declines, but by three months of age normal infants begin to synthesize their own IgG.

• In some infants, however, IgG synthesis may not begin until they are 2 to 3 years old.

• This delay has been attributed to poor T cell help.

• This results in a transient deficiency of IgG which can be treated with gamma-globulin

• Profound decrease in antibody producing plasma cells

• Low levels of all isotypes• Recurrent infections• Condition manifest late than

other immunodeficiency (teens or twenties)

• Late onset hypogammaglobulinemia

Common Variable immunodeficiency

Common variable immunodeficiency• Martha D., a 40-year-old woman, presents with recurrent

sinusitis requiring antibiotic treatment. She has had two hospitalizations within the past two or three years for bacterial pneumonia. She also reports symptoms of chronic diarrhea, abdominal pain, weight loss, and fatigue. Laboratory tests reveal evidence of malabsorption due to infection with Giardia lamblia. Serum immunoglobulin assessments reveal a significantly decreased level of IgG and a mildly decreased level of IgA, consistent with common variable immunoglobulin deficiency. She is treated with passive immunoglobulin therapy, and her IgG level increases to within normal range. She continues to receive immunoglobulin therapy and remains free of significant infection or diarrhea for several years thereafter.

Bruton’s X-linked agammaglobulinemia• Bruton’s X-linked agammaglobulinemia was named

after an American pediatrician, Dr. Ogden Carr Bruton. In 1952, Dr. Bruton described the clinical case of an 8-year-boy who had recurrent bacterial infections, including many episodes of pneumococcal sepsis. Dr. Bruton vaccinated the boy, the boy did not produce anti-bodies to any antigen and had undetectable levels of serum immunoglobulins. Dr. Bruton treated this patient with monthly injections of exogenous gamma globulin. The boy did not have any occurrences of sepsis over the 14 months during which he received injections. Because this condition was observed only in male patients, it was determined to be X-linked

Defects of T cellsCombined T and B cell disorder

and Severe Combined deficiencies

Deficiencies associated with defects lymphocyte activation and effector functions

Disease Functional Deficiencies Mechanism of DefectDefects in MHC expressionBare lymphocyte syndrome

Defective MHC class II expression and deficiency in CD4+ T cells; defective cell-mediated immunity and T-dependent humoral immune responses

Defects in transcription factors regulating MHC class II gene expression,

MHC class I deficiency Decreased MHC class I levels; reduced CD8+ T cells

Mutations in TAP1, TAP2

Defective T cell signalingProximal TCR signaling defects

Defects in cell-mediated immunity and T-dependent humoral immunity

Mutations in CD3 genes, CD45,

Familial hemophagocytic lymphohistiocytosesX-linked lymphoproliferative syndrome

Uncontrolled EBV-induced B cell proliferation, uncontrolled macrophage and CTL activation, defective NK cell and CTL function

Mutations in SAP

Perforin deficiencies Uncontrolled macrophage and CTL activation, defective NK cell and CTL function

Mutations in PERFORIN

Granule fusion Uncontrolled macrophage and CTL activation, defective NK cell and CTL function

Defective cytotoxic granule exocytosis;)

Defects in T cell Activation

Disease Functional Deficiencies Mechanism of DefectDefects in cytokine signalingX-linked SCID Marked decrease in T cells; normal or

increased B cells; reduced serum IgCytokine receptor common γ chain mutations; defective T cell development in the absence of IL-7-derived signals

Autosomal recessive forms

Marked decrease in T cells; normal or increased B cells; reduced serum Ig

Mutations in IL2RA, IL7RA, JAK3

Defects in nucleotide salvage pathwaysAutosomal recessive SCID due to ADA deficiency

Progressive decrease in T, B, and NK cells; reduced serum Ig

ADA deficiency caused by mutations in the gene, leading to accumulation of toxic metabolites in lymphocytes

Autosomal recessive SCID due to PNP (purine nucleoside) deficiency

Progressive decrease in T, B, and NK cells; reduced serum Ig

PNP deficiency caused by mutations in the gene, leading to accumulation of toxic metabolites in lymphocytes

Defects in V(D)J recombinationRAG1 or RAG2 deficiency recombination ; (Omenn’s syndrome)

Decreased T and B cells; reduced serum Ig; absence or deficiency of T and B cells

Cleavage defect during V(D)J recombination; mutations in RAG1 or RAG2

Defective thymus developmentDefective pre-TCR checkpoint

Decreased T cells; normal or reduced B cells; reduced serum Ig

Mutations in CD45,

DiGeorge syndrome Decreased T cells; normal B cells; normal or reduced serum Ig

22ql 1 deletion;

Severe Combined Immunodeficiencies

Congenital Thymic Aplasia Thymic hypoplasia

• Di George's syndrome: autosomal dominant, caused by deletions of various sizes in chromosome 22

• Most clearly defined T-cell immunodeficiency

• Both thymus & parathyroid fail to develop properly: abnormal development of the fetus (3rd and 4th pharyngeal pouch) during the 6-10 wk of gestation (forming parathyroid, thymus, lips, ears and aortic arch)

• Circulating T cells are decreased• Circulating B cells normal• Serum antibodies are normal or

decreased• Associated features: • Hypoparathyroidism (tetany;

seizures in new born)• Absent thymic shadow on

radiograph• Congenital heart defects, low set

notched ears and fish shaped mouth

DiGeorge SyndromeSmall Thymus, Low T Cell Development

BoneMarrow Thymus Thymus Peripheral LN

Congenital Thymic Aplasia; Thymic hypoplasia

• Early life infections with• Extracellular Bacteria • Viral infections: CMV, EBV,

Varicella• Fungi: Pneumocystis and Candida

• Treatment: • Patients may be treated with a

thymic graft.• Thymic graft from an early fetus

(13-14 wk gestation) used for treatment where as older grafts may result in GVH reaction.

• In severely immunodeficient DiGeorge patients, live vaccines may cause progressive infections.

Hyper IgM syndrome

• Individuals with this type of immunodeficiency have low IgA, IgE and IgG concentrations with abnormally high levels of IgM.

• These patients cannot make a switch from IgM to other classes which is attributed to a defect in CD40L on their CD4 cells.

• Absence of co-stimulatory signal of CD40-CD40L inhibits B cell response to T-dependent antigens

• B cell response to T- independent antigen is unaffected accounting for the production of IgM

• No class switching and failure to produce germinal centers

• They are very susceptible to pyogenic infection and should be treated with intravenous gamma-globulins.

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Helper T cell mediated activation of B cells

Defects in IgG production and affinity maturation in hyper

IgM syndrome

• No class switching• No somatic hypermutation• Increased susceptibility to

extracellular bacteria and some fungal infections

Severe Combined Immunodeficiency (SCID

• Defective lymphoid progenitor cells ; both the T & B cell lineages are affected ; result in SCID

• Less common but are very severe. • Infants suffer from recurrent

infections especially by opportunistic microorganisms (bacterial, viral, mycotic, protozoan)

• Immunodeficiency is X-linked or autosomal

• Characterized by an absence of T cell and B cell immunity and absence (or very low numbers) of circulating T and B lymphocytes.

• Thymic shadows are absent on x-rays.

• Diagnosis is based on enumeration of T and B cells and immunoglobulin measurement.

• Treatment is by gene therapy or stem cell transplantation.

• SCID patient must not receive live vaccine as it will result in progressing disease

SCID Defect: ADA deficiency

• Adenosine deaminase (ADA) deficiency

• ADA: enzyme responsible for converting adenosine to inosine.

• Ada deficiency leads to accumulation of adenosine which results in production of toxic metabolites that interfere with DNA synthesis.

• Defects in adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) genes which results is accumulation of dATP or dGTP, respectively, and cause toxicity to lymphoid stem cells.

• The patients have defects in T, B and NK cells

• Clinical manifestations include skin, mouth & throat lesions, opportunistic fungal infections, chronic diarrhea, low levels of circulating lymphocytes

• Autosomal SCID patients with ADA deficiency have been treated with a retroviral vector transfected with the gene with some success.

SCID Defect: Common gamma chain of IL-2 R

• Common gamma chain of IL-2 R (present in receptors for IL-4, -7, -9, -15)

• X-linked severe SCID• IL-2R may be lacking in patients

thereby preventing signaling by IL-2 and other growth factor cytokines

• Lead to defect in the proliferation of T cells, B cells and NK cells.

• Clinical manifestations include skin, mouth & throat lesions, opportunistic fungal infections, chronic diarrhea, low levels of circulating lymphocytes

SCID Defect: Rag1 or Rag2 mutations• Rag1 or Rag2 gene nonsense

mutations• Total absence of B & T cells• Patients having both T and B cell

deficiency lack recombinase activating genes (RAG1 and 2) that are responsible for the T cell receptor and Ig gene rearrangements.

• These patients are athymic and are diagnosed by examining the TCR gene rearrangement.

• This is an autosomal recessive trait

• They also lack B cells although they do have Abs in early infant life because of passive transfer from mother. NK cells are normal in these patients.

• Omenn’s syndrome: increased susceptibility to opportunistic infections and clinical feature similar to GVH disease with rash, eosinophilia, diarrhea and enlargement of LN

• RAG-1 or RAG-2 defect can make some amount functional Rag protein. Allow small amount of VD-J recombination

X-linked SCID• Timmy K., a 4-month-old male, presents with severe diarrhea

andfailure to thrive. Over the past two months, he has had two episodes of ear infections requiring antibiotic therapy. Examination reveals a poorly nourished child with minimal tonsillar tissue and the presence of oral thrush. Blood tests reveal lymphocyte counts significantly below normal with an absence of T cells (CD3+) and NK cells (CD16+, CD56+) and significantly reduced numbers of B cells (CD19+).

• A further workup by an immunology consultant results in a diagnosis of X-linked SCID.

• The hematology/immunology trans-plant team is notified, and the patient receives a bone marrowtransplant.B.

B- and T-cell disorders associated with other diseases

Disease Defect Presentation LabsAtaxia-telangiectasia Defect in DNA repair

enzymes.Triad: Cerebellar defects (ataxia), Spider angiomas (telangiectasia), IgA deficiency.

IgA, IgE deficiency.Normal IgM

Wiskott-Aldrich syndrome

X-linked recessive defect. Progressive deletion of B and T cells.TCR-dependent actin-cytoskeletal rearrangements are defective because of mutations in WASP

Triad (TIE): Thrombocytopenic purpura, Infections, Eczema.

↑ IgE, IgA; ↓ IgM.

Ataxia-Telangiectasia

• Deficiency of T cells associated with a lack of coordination of movement (ataxis) and dilation of small blood vessels of the facial area, eyes (telangiectasis).

• Defective CMI: T-cells and their functions are reduced to various degrees.

• B cell numbers and IgM concentrations are normal to low.

• IgG is often reduced and IgA is considerably reduced (in 70% of the cases).

• There is a high incidence of malignancy, particularly leukemia, in these patients.

• The defects arise from a breakage in chromosome 14 at the site of TCR and immunoglobulin heavy chain genes.

• Mutations in genes coding for DNA repair enzymes

Wiskott-Aldrich Syndrome

• Defect in cytoskeletal glycoprotein, CD43

• Mutant gene encodes a protein involved in actin filament assembly in cytskeleton of all hematopoietic cells

• Defect in cell migration and signal transduction

• Gradual loss of humoral and cellular responses: inability of T cells to provide help to B cells

• Associated with normal T cell numbers with reduced functions, which get progressively worse.

• TRIAD: (TIE) Thrombocytopenia, Infections, Eczema

• IgM reduced, IgG normal, IgA & IgE elevated

• X-linked disorder• Boys with this syndrome develop

severe eczema, Petechia (due to platelet defect) and bleeding from thrombocytopenia. They respond poorly to bacterial polysaccharide antigens (pneumococci) and are prone to pyogenic infection and respiratory infections.

MHC Deficiencies

MHC-II Deficiency• Circulating T cells normal• decreased CD4 T cell numbers• Circulating B cells normal• Serum Ig normal or decreased• Associated features:

– Bare Lymphocyte Syndrome, lack of T-cell responses to antigens, Hepatic disease from chronic cryptosporidia or CMV infection

MHC-I Deficiency• TAP 1/2 Deficiency• Circulating T cells: decreased

CD8, normal CD4• Circulating B cells an serum Ig

normal• Associated features:

– respiratory infections, vasculitis, with few viral infections

Reading

• Chapter 12 Abbas and Lichtman; 3rd or 4th edition

• Robbins 8th edition , Chapter 6

Immunodeficiency Diseases March 2014 (1)

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