IMMUNODEFICIENCIESAGE AND HEALTH DEPENDENTIMMUNOSUPPRESSIVE DRUGS

• INHERITED– Loss of function mutation

of genes of the immune system

– Enhanced susceptibility to infections

– Particular types of pathogens depending on the gene defect

– Did not stand out until 1950 - antibiotics

• ACQUIRED– Due to infectious

diseases – AIDS– Other virus infections– Malnutrition– Artificial

immunosuppression• Drugs• Radioactive irradiation

INHERITED IMMUNODEFICIENCIES

• MOST ARE RECESSIVE MUTATION OF SINGLE GENES– Dominant traits have been eliminated from the population– Autosomal genes

• Disease in homozygous children • Heterozygous children are carriers

– X-linked genes• Single gene defect causes disease in males• Single gene defect in females renders the affected woman carrier

– Mutation in the IFNγ receptor results in binding without intracellular signaling - dominant

DISSEMINATED INFECTION BY THE BCG STRAIN OF Mycobacterium USED FOR VACCINATION

Numerous Immunodeficiency loci reside on the X chromosome

CGD: Chronic Granulomatous Disease

WAS: Wiscott-Aldrich Syndrome

SCID: Severe Combined Immunodeficiency

XLA: X-linked Agammaglobulinemia

XLP: X-linked Lymphoproliferative Disease

XLHM: X-linked Hyper-IgM Syndrome

AGE-DEPENDENT DEVELOPMENT OF THE IMMUNE SYSTEMS

0 3 32 546 9 1 6months years

ADULT AGING

Maternal IgG

BEFORE BIRTH AFTER BIRTH

IgAmilk IgM

IgG

IgA

Immunodeficiency

TYPES OF INHERITED IMMUNE DEFICIENCIES

• ANTIBODY DEFICIENCY

• - recurrent sinopulmonary and GI infections beginning after 3-4 mo.

– B cell development• (XLA, IgA deficiency)

– B – T cell collaborations • CD40 ligand, hyper IgM

• T CELL DEFICIENCY

• - SCID, opportunistic infections beginning early in infancy

– T cell development• IL-7/Jak3• Cytoskeleton

– Thymus epithelial cells• DiGeorge syndrome

– Purin catabolism– DNS repar enzyme defect– MHC class II synthesis

blockade

• PHAGOCYTIC SYSTEM– CD18 (CR3, CR4, LFA1)– NADPH oxidase (CGD)– Vesicular fusion

• COMPLEMENT SYSTEM• some infections, primarily with

encapsulated organisms and Neisseriae

– Soluble and membrane factors – C3– C1 – C4– Komplement inhibitors

TYPES OF INHERITED IMMUNE DEFICIENCIES 2.

• X-LINKED AGAMMAGLOBULINEMIA XLA– Bruton’s agammaglobulinemia– Mutation in the Bruton tyrosine kinase (Btk) gene– Expressed in B cell, monocytes– Essential for B cell activation and development– NO B CELLS IN THE PERIPHERY – block at pre-B – Carrier mother XX HEALTHY non-random inactivation

of X in B cells– Son XY DISEASE Son XY HEALTHY– Increased susceptibility to bacteria – antibiotics and

enteroviruses– Pyogenic bacteria – permanent tissue demage caused by

enzyme release from bacteria and phagocytes • Haemophilus, Streptococcus, Staphylococcus,

– bronchiectasis, chronic lung disease – monthly injections of Gamma glob. or passive antibody isolated from plasma of healthy donors

ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA

SELECTIVE IgA DEFICIENCY

1/800- Chronic lung disease, no increased susceptibility to infections- Tendency to develop respiratory and gastrointestinal allergies and autoimmunity- Over 40% of patients have anti-IgA antibodies – blood products containing IgA can cause severe allergic response. -Some are related to MHC class III region

antigantigeen n bindingbinding

mIg moleculemIg molecule

HH HH

LL LL

VV VV VV VV

jelátviteljelátvitel

Ig-Ig-/Ig-/Ig-heterodimerheterodimer

THE IgM B-CELL RECEPTOR

Lyn

KinKinasesasesSykSyk

BtkBtk

SHP-1PhosphatasesPhosphatases

SLP-65/BLNKSLP-65/BLNKPLCPLC

HS1HS1VavVavAdaptors +Adaptors +

substratessubstrates

HYPER IgM SYNDROME

TB

NO Cytokine production

Isotype swithSomatic hypermutation

T-dependent Ag

Th1 macrophage

IFNγ

CD40CD40L inflammation

NO Cytokine production

• HYPER IgM SYNDROME– Defect of the DC40L membrane cytokine gene– X-linked, disease in males– No specific antibody response to T-dependent antigens

• low IgG, IgA, IgE• Sensitivity to pyogenic bacteria

– No germinal center formation– No macrophage activation by T cells CD40 – CD40L– No inflammation end leukocyte mobilization– No leukocytosis but neutropenia

• sores and blisters in the mouth and throat• injection of GM-CSF

– Susceptibility to pyogenic bacteria/opportunistic infection• Antibiotics• Monthly gammaglobulin

DIMINISHED ANTIBODY PRODUCTION AS A RESULT OF INHERITED DEFECT OF T CELL HELP

Lack of germinal centers in lymph nodes ofX-linked Hyper-IgM syndrome patients

MUTATION OR FUNCTIONAL INACTIVATION OF SOLUBLE COMPLEMENT PROTEINS RESULTS IN IMMUNODEFICIENCY

B-factorD-faktor

Pyogenic infections immune complex disease

Alternative

Properdin

C5C6C7C8C9

C3I-factorH-faktor

Classical Lectin

Neisseria-infection immune complex disease

C1Inh

HANE*

Neisseria-infection severe pyogenic infections

Pyogenic infections immune complex disease

C1 MBLMASP

C2C4

*HANO - hereditary angioneurotic edema

Stabilizes alternative C3convertase

• DEFICIENCY OF C3 OR ITS ACTIVATION– Susceptibility to pyogenic bacteria – inefficient opsonization

• DEFICIENCY OF C5-C9– Neisseria – NO complement mediated lysis

• DEFICIENCY OF EARLY C1-C4 – No C3b and C4b fragments No CR1-mediated erythrocyte transport of

immune complexes– Accumulation of immune complexes in blood, lymph, extracellular fluid

deposition in tissues tissue demage macrophage activation inflammation

• DEFICIENCY IN COMPLEMENT INHIBITORY FACTORS– I factor – uncontrolled C3 C3b C3 depletion inefficient opsonization– Properdin – reduced deposition of C3 increased susceptibility to Neisseria– Decay Accelerating Factor DAF or CD59 MAC inhibitor – autoimmune-like

condition lysis of autologous erythrocytes paroxysmal nocturnal hemoglobulinuria

– C1 inhibitor – uncontrolled activation of the classical pathway vasoactive C2 accumulation of fluid in tissues – epiglottal swelling may lead to death by suffocation

DEFECTS IN COMPLEMENT COMPONENTS IMPAIR ANTIBODY RESPONSES

ACCUMULATION OF IMMUNE COMPLEXES

Intra va sc ula rhem olysis

(c o m p le m e nt re c e p to r 1)C R1 SLE* -a ssoc ia tion

Pyo g enicinfec tio ns

(De c a y Ac c e le ra ting Fa c to r) (Ho m o lo g o us Re stric tio n Fa c to r) (M e m b ra ne inhib ito r o f Re a c tive Lysis)

DAFHRFM IRL

*SLE- syste m ic lup us e rythe m a to sus

(c o m p le m e nt re c e p to r 3,4)LFA

MUTATION OF MEMBRANE BOUND COMPLEMENT PROTEINS RESULTS IN IMMUNODEFICIENCY

MIRL = CD59

• CD18 DEFICIENCIA/LEUKOCITA ADHÉZIÓ– A CR3, CR4 és LFA-1 közös β-alegysége – Gátolt fagocita miráció a vérből a fertőzés

helyére– Az opszonizált baktériumok felvétele és

lebontása gátolt – Perzisztáló fertőzések extracelluláris

baktériumokkal • Gennykeltő baktériumok• A sebgyógyulás károsodása, súlyos íny gyulladás

A FAGOCITA FUNKCIÓK KÁROSODÁASFOKOZOTT ÉRZÉKENYSÉG A BAKTERIÁLIS FERTŐZÉSEKKEL

SZEMBEN

• DEFICIENCY OF CD18/LEUKOCYTE ADHESION (LAD)– Common β-subunit of CR3, CR4 and LFA-1– Blocked phagocyte migration from blood to infection site– Inhibited uptake and degradation of opsonized bacteria – Persistant infection with extracellular bacteria

• Pyogenic infections• Defect in wound healing, severe inflammation of the gumsLethal within the first decade of life without bone marrow

transplant

DEFECTS IN PHAGOCYTE FUNCTIONENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS

Omphalitis in LAD I patient

CHRONIC GRANULOMATOUS DISEASE – CGD

Mutation of NADPH oxidase – any of the 4 subunitsNO superoxid O2- radical antibacterial activity is compromised Chronic bacterial infections – granuloma formationAspergilus pneumoniaIFN-gamma improves resistance. Mechanism??Defect of glucose-6-phosphate dehydrogenase and myeloperoxidase less severe phenotype

DEFECTS IN PHAGOCYTE FUNCTIONENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS

CGD patient with

skin infections

due to Serratia

marcescens

CHÉDIAK-HIGASHI SYNDROME Abnormal large granules in a variety of cells leading to:

-hypopigmentation/partial albinism hair and eyes -severe immunodeficiency

Defect in vesicle fusion mechanism phagocytosed material is not delivered to lysosomesPersistent and recurrent bacterial infections

Defective gene: CHS1 located on 1q42-43Defective gene: CHS1 located on 1q42-43

DEFECTS IN PHAGOCYTE FUNCTIONENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS

FcR CR1 CR3

chemokinereceptors

Cytosceletalchanges,

chemotaxis,homing

enzyme containingvesicles

adhesionmolecules

NADPHoxidasecomplex

O2

H2O2

OCl-N-chloramines

O2-

Subunits of theenzyme complex

(CGD)

LAD1,2

Complementdeficiency

Lack of vesicularmembrane proteins(Chediak Higashi

syndrome)

MyeloperoxidaseG6P-dehidrogenase

deficiency

Antibody deficiency

Lack of signaling

molecules

C3fragment

IgG

Pathogen

intracellularsignaling

DEFECTS OF MACROPHAGE FUNCTIONS CAUSING IMMUNODEFICIENCIES

T CELL IMMUNODEFICIENCIES

• Persistent and recurrent infections with a broader range of pathogens than patients with B cell deficiences

• Neither T cell-dependent antibody response nor cellular immunity are functional

DEFECT IN T CELL FUNCTIONST cells are involved in all aspects of adaptive immunity

SEVERE COMBINED IMMUNODEFICIENCYSCID

Treatment:Treatment:Bone marrow transplantation, preferably from a Bone marrow transplantation, preferably from a histocompatible siblinghistocompatible siblingGene therapyGene therapy

• X-SCID – The common γ-chain of interleukin receptors is mutated IL-7 receptor• Autosomal SCID – mutation of Jak3 kinase IL-7 receptor-mediated signaling • Defect in the catabolism of purin bases – autosomal

– Adenosine deaminase (ADA) mutation – mental retardation – Purin nucleotide phosphorilase (PNP)

• Accumulation of purin metabolites • Highly toxiC for developing T lymphocytes, less toxic for developing B lymphocytes

• Mutation of RAG enzymes – autosomal (Omen syndrome T- B- SCID)– No or little somatic gene rearrangement (RAPIDLY FATAL)– No circulating peripheral lymphocytes or very narrow repertoire

• Mutation of a DNA repair enzyme – autosomal – DNA-dependent protein kinase (DNA-PK) involved in the cleavage of hairpins in somatic gene

rearrangement • Bare lymphocyte syndrome – inhibited MHC synthesis

– No CD4+ T cell response– CIITA co-activátor, RFX promoter binding protein or other transcription factor mutation

• DiGeorge syndrome– Development of thymic epithelial cells is inhibited – T cell development is inhibited

• Mutation of TAP transporter– Selective loss of CD8+ T cell responses – no SCID phenotype

• Wiskott-Aldrich syndrome WAS – X-kinked – Thrombocytes and lymphocytes – WAS protein (WASP)– Rearrangement of cytoskeleton upon T cell activation in the polarized contact with B cells,

macrophages and target cells

SEVER COMBINED IMMUNODEFICIENCIESThe SCID phenotype can be caused by various gene defects

• Defect in the catabolism of purin bases – autosomal (T- B-)– Adenosine deaminase

(ADA) mutation – mental retardation

– Purin nucleotide phosphorilase (PNP)

• Accumulation of purin metabolites

• Highly toxiC for developing T lymphocytes, less toxic for developing B lymphocytes

SEVER COMBINED IMMUNODEFICIENCIESThe SCID phenotype can be caused by various gene defects

BONE MARROW

LYMPHOID PRECURSOR

ADAPNP

BRUTON

CVID

THYMUS

PERIPHERAL LYMPHOID TISSUES

X-SCID

DiGeorge

MHC II

Hyper IgM

IgA

MUTATIONS IN IMMUNODEFICIENCIES AND LYMPHOCYTE DEVELOPMENT

• Wiskott-Aldrich syndrome WAS – X-kinked – Thrombocytes and lymphocytes – WAS protein (WASP)

abnormally small platelets, B-cells normalpyogenic and opportunistic infectionssevere infection with varichella (chicken pox) and herpes simplex

- Eczema- No antibodies to ccarbohydrate antigens– Rearrangement of cytoskeleton upon T cell activation in the

polarized contact with B cells, macrophages and target cells

IL-7IL-7 receptor α-chain

PI3KSrc

StatStat

AdaptersSTAM

Transcription Chromatin remodeling

VDJ recombinaion

Trophic

Prolipherative

Jak1Jak3

c-myc, cyclinD1

bcl-2

Pyk2

gamma-c

IL-7 RECEPTOR-MEDIATED SIGNALING

EARLY DIFFERENTIATION OF B AND T LYMPHOCYTESBefore gene rearrangements

DiGeorge Syndrome• Conotruncal cardiac malformation• Hypoparathyroidism• Thymic hypoplasia leading to variable

immunodeficiency• Other features:

• Characteristic facies• Deletion in 22q11 in > 80%• Affected gene(s) is a transcription factor in the

T-box family called Tbx1

Severe Combined Immunodeficiency Syndromes (SCID)

• X-linked SCID (c deficiency)• Jak3 kinase deficiency• Adenosine deaminase deficiency• Purine nucleoside phosphorylase

deficiency• Bare lymphocyte syndrome• RAG1 and RAG2 deficiency