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Immunodeficiency. Primary (congenital) immunodeficiencies: inherited disorders that arise from a genetic defect Secondary immunodeficiencies: arise from extrinsic causes Malnutrition Irradiation Infections Immunosuppressive therapy. How Immunodeficiency Diseases Present.

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immunodeficiency
Immunodeficiency
  • Primary (congenital) immunodeficiencies: inherited disorders that arise from a genetic defect
  • Secondary immunodeficiencies: arise from extrinsic causes
    • Malnutrition
    • Irradiation
    • Infections
    • Immunosuppressive therapy
how immunodeficiency diseases present
How Immunodeficiency Diseases Present
  • Recurrent or chronic pyogenic (pus-forming) infections
    • These indicate defects in
      • Antibodies and/or B cells
      • Complement components
      • Phagocytes
    • Common agents are encapsulated bacteria
      • Streptococcus pneumoniae
      • Neisseria meningitidis
      • Staphylococcus aureus
      • Haemophilus influenzae
    • Common clinical manifestations
      • Bacterial pneumonia
      • Otitis media
      • Sinusitis
      • Meningitis
      • Osteomyelitis
      • Infections with gram-negative enterics
how immunodeficiency diseases present1
How Immunodeficiency Diseases Present
  • Recurrent or chronic opportunistic infections
    • These indicate defects in T cells
    • Common agents
      • Viruses, e.g. rotavirus, HIV
      • Fungi, e.g. Candida, Pneumocystis jiroveci
      • Protozoans, e.g. Toxoplasma
      • Atypical mycobacteria
    • Leads to combined deficiency of CMI and humoral immunity
  • Cancer
    • Usually indicates T cell deficiency
    • EBV, Kaposi sarcoma
how immunodeficiency diseases present2
How Immunodeficiency Diseases Present
  • Diseases that present as antibody deficiencies
    • X-linked agammaglobulinemia
    • Selective IgA and IgG subclass deficiencies
    • Hyper IgM syndrome
    • Common variable immunodeficiency
    • Transient hypogammaglobulinemia of infancy
  • Diseases that present as T cell or combined deficiencies
    • SCID
    • DiGeorge syndrome
    • Hereditary ataxia-telangiectasia
    • Wiskott-Aldrich syndrome
  • Phagocytic cell deficiencies
    • Chronic granulomatous disease
    • Leukocyte adhesion deficiency
    • Chédiak-Higashi disease
    • Hyper IgE (Job) syndrome
  • Complement deficiencies
    • Hereditary angioedema
    • Paroxysmal nocturnal hemoglobinuria
    • Component deficiencies
x linked infantile bruton s agammaglobulinemia xla
X-linked Infantile (Bruton’s) Agammaglobulinemia (XLA)
  • Males only; rare
  • btk gene defect
  • First presents at 5-6 months of age
  • Repeated pyogenic infections that don’t respond to antibiotics, Giardia lamblia
  • Passive immunity from mom has dissipated
  • Near absence of all antibodies: no response to vaccines, no isohemagglutinins
  • Scant lymphoid tissue
  • By 20-30 y, bronchiectasis may cause death
  • T cells OK, so live vaccines OK

Antibody deficiencies

selective iga deficiency
Selective IgA Deficiency
  • Common in Caucasians
  • Serum IgA <50 mg/ml
  • Sinopulmonary infections, celiac disease, immune complex disease
  • May be asymptomatic
  • May progress to CVID
  • Persons with IgA deficiency may possess IgE directed toward IgA
    • Wash those RBCs before transfusion!

Antibody deficiencies

selective igg subclass deficiency
Selective IgG Subclass Deficiency
  • Total serum IgG may be normal
  • IgG3 deficiency most common in adults
  • IgG2 deficiency most common in children
  • May lead to increased bacterial infections, or have no problems

Antibody deficiencies

hyper igm syndrome
Hyper-IgM Syndrome
  • Low levels of IgG and IgA with increased levels of IgM
  • IgM autoantibodies to neutrophils, platelets, tissue antigens
  • B cells can’t class-switch
  • X-linked (70%)
    • T cell defect in CD40L
    • No T cell activation of macrophages
    • Defective CMI  P. jiroveci
  • Autosomal recessive (30%)
    • Defect in CD40 gene in B cells and APCs
    • Defect in activation-induced cytidine deaminase (AID) gene in the B cell

Antibody deficiencies

common variable immunodeficiency cvid
Common Variable Immunodeficiency (CVID)
  • Common variable hypogammaglobulinemia
  • Males and females
  • Usual onset 15-35 y
  • May follow EBV infection
  • Associated with selective IgA deficiency
  • Low serum IgG and IgA, low or normal IgM, low or normal B cell count
  • Mothers cannot confer passive protection on infants
  • Marked by
    • Pyogenic bacterial infections
    • Autoimmune diseases, especially pernicious anemia
    • Giardiasis
    • Malignant neoplasms
  • Variable defects

Antibody deficiencies

transient hypogammaglobulinemia of infancy
Transient Hypogammaglobulinemia of Infancy
  • Males and females
  • Presents at 5-6 months
  • May persist through 2-3 years of age
  • IgG absent, IgM and IgA normal
  • B cells are normal
  • No class switching to IgG due to TH defect
  • TH defect precludes live viral vaccines!
  • Normal numbers of B cells in blood, unlike XLA

Antibody deficiencies

treatments for antibody deficiencies
Treatments for Antibody Deficiencies
  • Broad-spectrum antibiotics
  • Intravenous immune globulin – contains mostly IgG
  • Do not treat selective IgA deficiency with IVIG
    • Patients may possess IgE specific for IgA
    • Administration of IgA may cause anaphylaxis
    • If your patient is both IgG and IgA deficient, correct the IgG deficiency with an IVIG prep that contains no IgA – Gammagard S/D
    • Treat IgA deficiency with antibiotics

Antibody deficiencies

severe combined immunodeficiency scid
Severe Combined Immunodeficiency (SCID)
  • Heterogeneous disorder with defects in CMI and antibody
  • Patients susceptible to all types of infections – rotavirus, CMV, candidiasis, Pneumocystis jiroveci
  • Diarrhea and pneumonia
  • Vaccination with live microbes is lethal
  • Symptoms occur earlier than in XLA
  • Fatal before age 1 year if untreated
  • Treat with bone marrow transplant
  • There are three phenotypes: T–B+, T–B–, T+B+

T/combined

severe combined immunodeficiency scid1
Severe Combined Immunodeficiency (SCID)
  • T–B+ subgroup
    • X-linked
      • Defect in the g chain of the receptor for IL-2, 4, 7, 9, and 15
      • Recessive mutation – heterozygous females are phenotypically normal carriers

Failure to activate transcription of specific genes

T/combined

severe combined immunodeficiency scid2
Severe Combined Immunodeficiency (SCID)
  • T–B+ subgroup
    • Autosomal recessive
      • Defect in the  chain of IL-7 or in the JAK3 tyrosine kinase
      • JAK3 tyrosine kinase is responsible for transmitting signals from the  chain of the receptors for IL-2, 4, 7, 9, 15

T/combined

scid continued
SCID continued
  • T-B- subgroup
    • Defects in adenosine deaminase (ADA)
      • Accumulation of intracellular S-adenosylhomocysteine and dATP
      • T and B lymphocytes are particularly susceptible
        • Lack compensatory 5’-nucleotidase
      • Treat with gene therapy, continuous enzyme supplementation, or bone marrow transplant
    • RAG-1 and RAG-2 deficiencies
      • Stops B and T maturation at pre-B and pre-T stages

T/combined

scid continued1
SCID continued
  • T+B+ subgroup
    • Bare lymphocyte syndrome
      • Cells lack MHC class II
      • No collaboration between APCs and TH cells
    • Class I MHC/TAP deficiency
      • Defect in TAP transporter gene
      • No loading of processed peptide into MHC class I groove
      • Empty MHC class I molecule is unstable and not expressed on APC surface

T/combined

congenital thymic aplasia digeorge syndrome
Congenital Thymic Aplasia (DiGeorge Syndrome)
  • Thymus (and parathyroid) fails to develop from 3rd & 4th pharyngeal pouches
  • Few or no T cells
  • Hypocalcemic tetany 24 h due to hypoparathyroidism
  • Congenital defects in heart and kidneys
  • Hypertelorism, low-set ears, shortened philtrum

T/combined

digeorge syndrome continued
DiGeorge Syndrome continued
  • B cells present, but no IgG production
  • No live vaccines!
  • Not hereditary, deletion in chromosome 22
  • Immunodeficiency treated by bone marrow transplant
    • BMT may not be necessary
    • T cell function may be normal by age 5 years
  • Nude mouse model

T/combined

hereditary ataxia telangiectasia
Hereditary Ataxia-Telangiectasia
  • Neurologic, immunologic, endocrine, hepatic and cutaneous abnormalities
  • Defective DNA repair gene
  • DNA breaks in chromosomes 7 and 14 encoding TCR and heavy chain go unrepaired
  • Presents at 18 months: wobbly gait (ataxia)
  • Telangiectasia (dilated capillaries) appear on skin and in eyes by 6 y
  • Severe sinus and lung infections
  • Autoimmune disorders and cancer

T/combined

wiskott aldrich syndrome
Wiskott-Aldrich Syndrome
  • X-linked
  • wasp gene defect coding for cytoskeletal protein
    • Decreased signal transduction through adapter proteins
    • Accelerates Fas-mediated lymphocyte apoptosis
  • Presents at ~20 months
    • Thrombocytopenia leading to bleeding disorder
    • Small platelets
    • Low IgM, normal IgG, high IgA and IgE
    • Eczema
    • Pyogenic and opportunistic infections
    • Cannot respond to polysaccharide vaccines
  • Tx: antibiotics, anti-virals, bone marrow transplant
  • Life expectancy 3 y without antibiotics, 30 y with antibiotics but without immune reconstitution
  • Death due to lymphoid malignancy

T/combined

chronic granulomatous disease cgd
Chronic Granulomatous Disease (CGD)
  • Phagocytes lack functional NADPH oxidase  no superoxide, no peroxide, leads to intracellular survival of fungi and bacteria
  • Usual onset early childhood
  • 2/3 of cases are X-linked
  • Signs and symptoms
    • Repeated infections by catalase positive bacteria and fungi
      • Staphylococcus, Serratia, Burkholderia, Aspergillus, Candida
    • Granulomas
    • Pneumonia
    • Lymphadenitis
    • Abscesses in skin, liver and viscera
  • Tx
    • Antimicrobials, aggressive immunization
    • IFN
  • NBT test for diagnosis
    • CGD phagocytes fail to reduce NBT to formazan
    • In CGD phagocytes, there’s no color change from yellow to purple

Normal

CGD

Phagocyte defects

leukocyte adhesion deficiency
Leukocyte Adhesion Deficiency
  • LAD I
    • Defective CD18 (an integrin b chain) common to LFA-1 and CR3
    • No extravasation
    • Leukocytosis
    • No pus formation
    • No phagocytosis of microbes opsonized by complement
    • Severe infections spread rapidly, especially in mouth and GI tract
    • Treat with bone marrow transplant

CD15

  • LAD II
  • – Impaired fucose metabolism, e.g. sialyl Lewis X/CD15

Phagocyte defects

ch diak higashi disease
Chédiak-Higashi Disease
  • Defective granules in lysosomes and melanosomes
  • No intracellular killing
  • Signs and symptoms
    • Recurrent Staphylococcus, Streptococcus and Pseudomonas infections of skin, lungs, respiratory tract
    • Lymphoma-like infiltration of organs by leukocytes with giant cytoplasmic granules
    • Hypopigmentation because of faulty melanosomes
  • NK cell activity depressed
  • Tx: antibiotics, some BMT
  • Poor prognosis

Phagocyte defects

job s syndrome hyper ige syndrome
Job’s Syndrome (Hyper IgE Syndrome)
  • Immunologic features
    • Recurrent boils and cold staphylococcal abscesses
    • IgE and chronic eczema
    • Recurrent cystic lung disease with S. aureus and C. albicans
    • Mucocutaneous candidiasis
    • Otitis media
    • Eosinophilia
  • Non-immunologic features (not always present)
    • Bone fractures, other skeletal abnormalities
    • Coarse facial features, e.g. prominent brow
    • Joint hyperextensibility
    • Retained primary dentition
  • Causative effects variable
  • Tx: antibiotics and anti-fungals
  • Tx for eczema: corticosteroids, tacrolimus as last resort

Phagocyte defects

hereditary angioedema hae
Hereditary Angioedema (HAE)
  • Deficiency in C1 esterase inhibitor allows C1qr2s2 and plasmin to function unregulated
    • Type I (85%) – low levels of normal C1INH
    • Type II (15%) – normal or high levels of dysfunctional C1INH
  • Inherited or spontaneous mutations (acquired AE)
  • Unchecked activation of classical pathway consumes C4 and C2
  • Low levels of C4 are diagnostic
  • Signs and symptoms
    • Edema caused by C2 product from plasmin cleavage
    • Local edema of hands, face, arms, legs, genitals, buttocks
    • Edema of stomach, intestines, bladder causes abdominal pain, constipation or diarrhea, cramps, vomiting
    • Laryngeal edema can lead to suffocation
    • Edema may be preceded by tingling and erythema
    • Edema caused by stress or trauma, e.g. dental procedure

Complement defects

hereditary angioedema hae1
Hereditary Angioedema (HAE)
  • Prophylaxis before dental or surgical procedures
    • Fresh frozen plasma to replace C1INH
    • Danazol to increase C4
  • Treatment of on-going attack
    • Maintain airway
    • Narcotics for abdominal pain
    • IV fluids for hemodynamic stability

Complement defects

paroxysmal nocturnal hemoglobinuria pnh
Paroxysmal Nocturnal Hemoglobinuria (PNH)
  • Stem cell defect in GPI anchors of complement regulators that protect human cells
    • Decay-accelerating factor (DAF)
    • Homologous restriction factor (HRF)
    • CD59
  • Dark urine due to RBC lysis
  • Triad of symptoms
    • Anemia due to RBC lysis
    • Pancytopenia due to lysis of RBCs, WBCs, and platelets
    • Thrombosis in large vessels of liver, abdomen, brain, dermis
      • Thrombosis usual cause of death in PNH patients
      • Budd-Chiari syndrome – severe abdominal pain, enlarging liver, ascites
  • Additional signs and symptoms
    • Weakness, dyspnea, pallor, splenomegaly, iron deficiency, bleeding disorders, renal failure, severe headaches and eye pain (thrombotic vascular occlusion), chronic infections

Complement defects

paroxysmal nocturnal hemoglobinuria pnh1
Paroxysmal Nocturnal Hemoglobinuria (PNH)
  • Median survival 10 years
  • Variable age at onset
  • Dx
    • Flow cytometry to detect DAF and CD59 on peripheral blood cells
    • Sugar water test
      • Reduce salt concentration by adding isotonic sucrose
      • This causes lysis of PNH RBCs
    • Ham test
      • Acidify human serum to pH 6.2
      • Add RBCs from PNH patient
      • RBCs will lyse if GPI-deficient
  • Tx
    • For hemolysis: prednisone or eculizumab (Mab to C5)
    • For anemia: iron supplements, packed RBCs, erythropoietin
    • For thrombosis: heparin for emergencies, then maintain patient on Coumadin anticoagulant
    • Stem cell transplant for aplastic anemia or leukemia

Complement defects

complement component deficiencies
Complement Component Deficiencies
  • Deficiency in C5-C8
    • Increased incidence of Neisseria infections
    • Vaccination with MCV4 or MPSV4 helps prevent infections
  • Deficiency in C3, Factor H, Factor I
    • Recurrent pyogenic bacterial infections
    • Vaccinate against Neisseria meningitidis and Streptococcus pneumoniae
  • Deficiency in C1, C2, C4
    • Immune complex disease
    • SLE
  • Diagnosis of component deficiencies by CH50 assay
    • Perform dilution series of patient serum
    • Add serum dilutions to constant amount of sheep red blood cells coated with IgG
    • The complement titer is the reciprocal of the highest serum dilution to lyse 50% of the RBCs

Complement defects

secondary immunodeficiencies
Secondary Immunodeficiencies
  • Result from extrinsic causes
    • Poor nutrition is the leading cause world-wide
    • Cancer therapy, drugs to prevent graft rejection
    • Inflammatory bowel disease, skin burns – loss of antibodies
    • Surgical splenectomy
    • Infections of leukocytes

Secondary immunodeficiencies

secondary immunodeficiencies1
Secondary Immunodeficiencies
  • Acquired immunodeficiency syndrome (AIDS)
    • Caused by human immunodeficiency virus (HIV)
    • Transmission
      • Sexual contact
      • Transfer of blood products
      • Contaminated needles
      • Mother to child during pregnancy, birth, or breast-feeding
    • HIV infects all cells expressing CD4
      • TH cells
      • Monocytes/macrophages
      • Dendritic cells
      • Langerhans cells
      • Microglial cells

Secondary immunodeficiencies

secondary immunodeficiencies aids
Secondary Immunodeficiencies - AIDS
  • HIV also requires chemokine receptor as co-receptor
    • M-tropic viruses use CCR5
      • Prefer macrophage host cells
      • M-tropism early in disease
      • Persons with mutant CCR5 are HIV-resistant
    • T-tropic viruses use CXCR4
      • Prefer TH host cells
    • May be evolution from M-tropic to T-tropic as gp120 mutates
    • Early signs and symptoms
      • Fevers caused by IL-1 production
      • Night sweats
      • Diarrhea
      • Cachexia due to TNF release

Secondary immunodeficiencies

slide33

Secondary Immunodeficiencies - AIDS

  • Later
    • Profound loss of CD4+ TH cells
    • <200 TH cells/l
    • TH:Tc reverses to 1:2
    • Loss of humoral and cell-mediated immunity
  • Recurrent/opportunistic infections
    • Varicella-zoster – shingles
    • Herpes simplex – genital and anal lesions
    • Candida albicans – oral thrush
    • Cryptosporidium, Campylobacter, Salmonella, microsporidia – diarrhea
    • Pneumocystis, Mycobacterium, fungi – pneumonia
    • Toxoplasma – brain abscesses
    • CMV – esophageal ulceration, chorioretinitis, CNS
    • JC virus – progressive multifocal leukoencephalopathy
  • Lymphoma (EBV), Kaposi sarcoma (HHV-8), dementia, paralysis

Secondary immunodeficiencies

slide34

Kaposi’s sarcoma lesions

Pneumocystis jiroveci pneumonia

Cryptosporidium

CT

Cerebral toxoplasmosis

Small bowel

Secondary immunodeficiencies

slide35

Secondary Immunodeficiencies - AIDS

  • No vaccine, no cure
  • Tx: highly active antiretroviral therapy (HAART)
    • Combination therapy from these categories
      • Nucleoside reverse transcriptase inhibitors
      • Non-nucleoside reverse transcriptase inhibitors
      • Protease inhibitors
      • Inhibitors of viral entry – chemokine receptor antagonists, inhibitors of viral-cell membrane fusion
      • Integrase inhibitors under development – prevent integration of proviral DNA into host cell genome

Secondary immunodeficiencies

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