Immunodeficiency_Huwainan.pptx

I n t e r n a l M e d i c i n e D e p a r t m e n t
U n i v e r s i t a s M u h a m m a d i y a h S u m a t e r a U t a r a
2 0 2 3 / 2 0 2 4
I M M U N O D E F I C I E N C Y
H u w a i n a n N i s a N a s u t i o n
1 1 - B l o c k H e m a t o i m m u n o l o g y

Introduction
• Immunodeficiency can occur in any of the four major components of the immune system:
(1) B cells (antibody), (2) T cells, (3) complement, and (4) phagocytes
• In a patient with a history of infections that are unusually frequent, unusually severe, or
caused by unusual organisms
• Most immunodeficiencies are acquired, frequently caused by immunosuppressive medic
ations or diseases that suppress immunity, such as HIV/AIDS
• Congenital immunodeficiencies are important because:(1) the patterns of infections that a
re seen teach us how various immune components are supposed to function normally;
(2) recent technological advances have allowed us to better diagnose and treat
Levinson W, et al. 2022.
Immunodeficiency in
Review of Medical Microbiology
& Immunology: A Guide to Clin
ical Infectious Diseases
Seventeenth Edition
2

Classification
Sánchez-Ramón et al. 2019. Primary/Secondary Immunodeficiency Diseases in Oncohaematology. Frontiers in Immunology. 10
(586); Sánchez-Ramón S, et al. 2019. Primary and Secondary Immunodeficiency Diseases in Oncohaematology: Warning Signs,
Diagnosis, and Management. Front. Immunol. 10:586
3

P r i m a r y
I m m u n o d e f i c i e n c i e s
4

5
Primary Immunodeficiencies
Abbas AB, et al. 2014. Basic Immunology: Functions and Disorders of the Immune System. Philadelphia. Elsevier Inc.
• Primary immunodeficiencies are caused by genetic defects that
lead to blocks in the maturation or functions of different
components of the immune system
• 1 : 500 people in the United States and Europe
• Some of these disorders result in greatly increased susceptibility to
infections that may manifest early after birth and may be fatal
unless the immunologic defects are corrected
• Other congenital immunodeficiencies lead to mild infections and
may first be detected in adult life

6
Type of
immunodeficiency
Histopathology and
laboratory abnormalities
Common infectious
consequences
B cell deficiencies Absent or reduced follicles and
germinal centers in lymphoid
organs
Reduced serum Ig levels
Pyogenic bacterial infections, enteric
bacterial and viral infections
T cell deficiencies May be reduced T cell zones in
lymphoid organs
Reduced DTH reactions to
common antigens
Defective T cell proliferative
responses to mitogens in vitro
Viral and other intracellular microbial
infections (e.g.,
Pneumocystis jiroveci, atypical
mycobacteria, fungi)
Virus-associated malignancies (e.g.,
EBV associated lymphomas)
Innate immune
deficiencies
Variable, depending on which
component of innate immunity is
defective
Variable; pyogenic bacterial and viral
infections

7
Owen JA, et al. 2009. Kubi Immunology Seventh Edition. The Journal of Experimental Medicine. 206:2925-2935.

Defects in Lymphocyte Maturation
8

9
• Many primary immunodeficiencies are the result of genetic
abnormalities that cause blocks in the maturation of B lymphocytes,
T lymphocytes, or both
• Disorders manifesting as defects in both the B cell and T cell arms of
the adaptive immune system are classified as severe combined
immunodeficiency (SCID)
• 50% X-linked, affecting only male children
• > 99% of X-linked SCID are caused by mutations in the common γ (γc) chain signaling
subunit of the receptors for several cytokines, including interleukin-2 (IL-2), IL-4, IL-7, IL-9,
IL-15, and IL-21
• When the γc chain is not functional --> immature lymphocytes, especially pro-T cells, cannot
proliferate in response to IL-7 --> reduced survival and maturation of lymphocyte precursors
• γc chain is part of the receptor for IL-15 --> the major cytokine involved in NK cell proliferation
and maturation --> NK cells deficient
Defects in Lymphocyte Maturation-SCID

10
• The consequence of this block is:
Decrease in the
numbers of
mature T cells
Deficient cell
mediated
immunity
Defective
humoral
immunity
because of
absent T cell
help NK cells
also are deficient

11
• About half the cases of autosomal SCID are caused by mutations
in an enzyme called adenosine deaminase (ADA), which is
involved in the breakdown of adenosine
• Deficiency of ADA leads to:
• Accumulation of toxic purine metabolites in cells that are actively synthesizing DNA,
namely, proliferating cells
• Block in T cell maturation more than in B cell maturation
• Defective humoral immunity is largely a consequence of the lack of T cell helper
function

12
• Another important cause of autosomal SCID is mutation of the
gene encoding a kinase that is involved in signaling by the γc
cytokine receptor chain
• Rare cases of autosomal SCID are caused by mutations in the RAG1
or RAG2 gene, which encode the VDJ recombinase that is required
for immunoglobulin (Ig) and T cell receptor gene recombination and
lymphocyte maturation

13
Disease Functional deficiencies Mechanism of defect
X-linked SCID Markedly decreased T cells;
normal or increased B cells;
reduced serum Ig
Cytokine receptor common γ chain
gene mutations, defective T cell
maturation due to lack of IL-7 signals
Autosomal recessive SCID
due to ADA, PNP
deficiency
Progressive decrease in T and B
cells (mostly T); reduced serum Ig
in ADA deficiency, normal B cells
and serum Ig in PNP deficiency
ADA or PNP deficiency leads to
accumulation of toxic metabolites in
lymphocytes
Autosomal recessive SCID
due to other causes
Decreased T and B cells; reduced
serum Ig
Defective maturation of T and B cells;
may be mutations in RAG genes and
other genes involved in VDJ
recombination or IL-7R signaling
Severe combined immunodeficiency
(SCID)

14
• The most common clinical syndrome caused by a block in B cell
maturation is X-linked agammaglobulinemia (first described as
Bruton’s agammaglobulinemia) --> mutations in the gene
encoding a kinase called Bruton tyrosine kinase (BTK) -->resulting in
defective production or function of the enzyme
• B cells in the bone marrow fail to mature beyond the pre-B cell stage, resulting in a
marked decrease or absence of mature B lymphocytes and serum
immunoglobulins
Defects in Lymphocyte Maturation-B cell immunodeficiencies

15
X-linked
agammaglobulinemia
Decrease in all serum Ig isotypes;
reduced B cell numbers
Block in maturation beyond pre-B
cells, because of mutation in Bruton
tyrosine kinase (BTK)
Ig heavy-chain deletions IgG1, IgG2, or IgG4 absent;
sometimes associated with
absent IgA or IgE
Chromosomal deletion involving Ig
heavy-chain locus at 14q32
B cell immunodeficiencies

16
Abbas AB, et al. 2014. Basic Immunology: Functions and Disorders of the Immune System. Philadelphia. Elsevier Inc.; Cruse JM and Lewis RE. 2010.
Atlas of Immunology, Third Edition. USA. Taylor and Francis Group
• DiGeorge syndrome results from
incomplete development of the
thymus (and parathyroid glands)
and a failure of T cell maturation
• Patients with DiGeorge syndrome tend to
improve with age, probably because the
small amount of thymic tissue that does
develop is able to support some T cell
maturation
Defects in Lymphocyte Maturation-T cell immunodeficiencies

17
DiGeorge syndrome Decreased T cells; normal B cells;
normal or decreased serum Ig
Anomalous development of 3rd and
4th branchial pouches, leading to
thymic hypoplasia
T cell immunodeficiencies

18

19
• Treatment:
• Varies with the disease
• Hematopoietic stem cell transplantation, with careful matching of donor and
recipient to avoid potentially serious graft-versus-host disease
• For selective B cell defects, patients may be given pooled immunoglobulin from
healthy donors to provide passive immunity
• Ideal treatment for all congenital immunodeficiencies is to replace the defective
gene
• Successful gene therapy has been reported in patients with X-linked SCID; a
normal γc gene was introduced into their bone marrow stem cells, which were then
transplanted back into the patients
Defects in Lymphocyte
Maturation

Defects in LymphocyteActivation and Function
20

21
• X-linked hyper-IgM syndrome is characterized by defective B cell
heavy-chain isotype (class) switching, so that IgM is the major
serum antibody, and by severe deficiency of cell-mediated immunity
against intracellular microbes
• Caused by mutations in CD40 ligand (CD40L), the helper T cell
protein that binds to CD40 on B cells, dendritic cells, and
macrophages
• Failure to express functional CD40L --> defective T cell–dependent
B cell responses and affecting the enzyme activation-induced
deaminase (AID), such as isotype switching, in humoral immunity,
and to defective T cell–dependent macrophage activation in cell-
mediated immunity
Defects in Lymphocyte Activation and Function

22
• IgA deficiency caused by mutations of Ig heavy-chain constant
(C) region genes
• Common variable immunodeficiency (CVID) is a heterogeneous
group of disorders that represent a common form of primary
immunodeficiency
• Characterized by poor antibody responses to infections and reduced serum
levels of IgG, IgA, and often IgM
• Causes by defects in various genes involved in B cell maturation and
activation --> mutations in genes encoding receptors for B cell growth factors or
costimulators that play a role in T cell–B cell interactions
• Patients have recurrent infections, autoimmune disease, and lymphomas

23
• Bare lymphocyte syndrome is a disease caused by a failure to
express class II MHC molecules, as a result of mutations in the
transcription factors that normally induce class II MHC expression
• Class II MHC molecules display peptide antigens for recognition by
CD4+ T cells, and that this recognition is critical for maturation and
activation of the T cells
• Manifested by a profound decrease in CD4+ T cells, because of
defective maturation of these cells in the thymus and defective
activation in peripheral lymphoid organs

24
• Selective T cell deficiency caused by mutations affecting various
signaling pathways or cytokines and receptors involved in
differentiation of naive T cells into effector cells
• Depending on the mutation and the extent of the defect, affected
patients show severe T cell deficiency or deficiency in particular
arms of T cell–mediated immunity, such as in TH1 responses
(associated with atypical mycobacterial infections) and TH17
responses (associated with fungal and bacterial infections)

25

26
X-linked hyper IgM syndrome Defects in helper T cell–dependent B cell and
macrophage activation
Mutations in CD40 ligand
Common variable
immunodeficiency
Reduced or no production of selective isotypes or
subtypes of immunoglobulins; susceptibility to bacterial
infections or no clinical problems
Mutations in receptor for B cell growth
factors, costimulators
Defective class II MHC
expression: The bare lymphocyte
syndrome
Lack of class II MHC expression and impaired CD4+ T cell
activation; defective cell-mediated immunity and T cell–
dependent humoral immunity
Mutations in genes encoding
transcription factors required for class II
MHC gene expression
Defects in T cell receptor complex
expression or signaling
Decreased T cells or abnormal ratios of CD4+ and CD8+
subsets; decreased cell-mediated immunity
Rare cases due to mutations or deletions
in genes encoding CD3 proteins, ZAP-70
Defects in TH1 responses Decreased T cell–mediated macrophage activation;
susceptibility to intracellular microbial infection
Rare cases due to mutations encoding
the receptors for IL-12 or interferon-γ
Defects in TH17 responses Decreased T cell–mediated inflammatory responses;
susceptibility to infections with pyogenic bacteria and
mucocutaneous candidiasis
Rare cases due to mutations in genes
encoding STAT3, IL-17, IL-17R
X-linked lymphoproliferative
syndrome
Uncontrolled EBV-induced B cell proliferation,
uncontrolled macrophage and CTL activation, defective
NK cell and CTL function
Mutations in SAP

28
• Abnormalities in two components of innate immunity, phagocytes
and complement system
• Chronic granulomatous disease is caused by mutations in genes
encoding subunits of the enzyme phagocyte oxidase, which
catalyzes the production of microbicidal reactive oxygen species in
lysosomes
• As a result, neutrophils and macrophages that phagocytose microbes are unable
to kill the microbes
• The immune system tries to compensate for this defective microbial killing by
calling in more and more macrophages, and by activating T cells, which stimulate
recruitment and activation of even more phagocytes
• Collections of phagocytes accumulate around foci of infections by intracellular
microbes, but the microbes cannot be destroyed effectively --> granulomas
Defects in Innate Immunity

29
Delves PJ, et al. 2011. Roitt’s Essential
Immunology 12th Edition. USA. John Wiley
& Sons

30
• Leukocyte adhesion deficiency is caused by mutations in genes
encoding integrins, molecules required for the expression of
ligands for selectins, or signaling molecules activated by chemokine
receptors required to activate integrins
• Integrins and selectin ligands are involved in the adhesion of
leukocytes to other cells
• As a result of these mutations, blood leukocytes do not bind firmly
to vascular endothelium and are not recruited normally to sites of
infection

31
Delves PJ, et al. 2011. Roitt’s Essential Immunology 12th Edition. USA. John Wiley & Sons
• Deficiencies of complement regulatory proteins lead to various
syndromes associated with excessive complement activation
• Paroxysmal nocturnal hemoglobinuria (PNH): a defect in the
ability to synthesize these anchors, caused by a mutation in the X-
linked PIG-A, gene that encodes the enzyme required for adding N-
acetylglucosamine to phosphatidylinositol --> absence of these
complement regulators, lysis of the red cells
• ”Type II PNH” --> defect in decay accelerating factor (DAF)
• “Type III PNH”--> defect in DAF, CD59 (protectin) and homologous
restriction factor (HRF) deficiency

32
Delves PJ, et al. 2011. Roitt’s Essential Immunology 12th Edition. USA. John Wiley & Sons

33
Delves PJ, et al. 2011. Roitt’s Essential Immunology 12th Edition. USA. John Wiley & Sons;
Male D, et al. 2006. Immunology Seventh Edition. Philadelphia. Elsevier
• A defective gene for the C1 inhibitor is
associated with hereditary
angioedema and can lead to recurring
episodes of acute circumscribed
noninflammatory edema mediated by
a vasoactive C2 fragment
• The synthesis of C1 inhibitor can be
boosted by methyltestosterone or
preferably the less masculinizing
synthetic steroid, danazol; alternatively,
attacks can be controlled by giving ε-
aminocaproic acid to inhibit the
plasmin

34
• Chédiak-Higashi syndrome is an immunodeficiency disease in which the
lysosomal granules of leukocytes do not function normally
• The immune defect is thought to affect phagocytes and NK cells and manifests as
increased susceptibility to bacterial infection
• Rare patients have been described with mutations affecting Toll-like receptors
(TLRs) or signaling pathways downstream of TLRs, including molecules
required for activation of the nuclear factor κB (NF-κB) transcription factor
• Mutations affecting MyD88, an adaptor protein downstream of many TLRs, are
associated with severe bacterial (most often pneumococcal) pneumonia, and
mutations affecting TLR3 are associated with recurrent herpesvirus encephalitis
but apparently not other viral infections

35
Chronic granulomatous
disease
Defective production of reactive oxygen intermediates by
phagocytes
Mutations in genes encoding components of the
phagocyte oxidase enzyme, most often cytochrome b558
Leukocyte adhesion
deficiency-1
Absent or deficient expression of β2 integrins causing
defective leukocyte adhesion–dependent functions
Mutations in gene encoding the β chain (CD18) of β2
integrins
Leukocyte adhesion
deficiency-2
Absent or deficient expression of leukocyte ligands for
endothelial E- and P-selectins, causing failure of leukocyte
migration into tissues
Mutations in gene encoding a protein required for
synthesis of the sialyl-Lewis X component of E- and P-
selectin ligands
Complement C3 deficiency Defect in complement cascade activation Mutations in the C3 gene
Complement C2, C4
deficiency
Deficient activation of classical pathway of complement leading
to susceptibility to infection anddevelopment of lupus-like
disease
Mutations in C2 or C4 genes
Chédiak-Higashi syndrome Defective lysosomal function in neutrophils, macrophages and
dendritic cells, and defective granule function in natural killer
cells
Mutation in a gene encoding a lysosomal trafficking
regulatory protein
Herpes simplex virus 1 (HSV-
1) encephalitis
Defective antiviral immunity in the CNS Mutations in gene encoding TLR3
Recurrent bacterial
pneumonia
Defective innate immune responses to pyogenic bacteria Mutations in gene encoding MyD88

LymphocyteAbnormalitiesAssociated
withOther Diseases
36

37
• Wiskott-Aldrich syndrome is characterized by eczema, reduced
blood platelets, and immunodeficiency
• This X-linked disease is caused by a mutation in a gene that
encodes a protein that binds to various adaptor molecules and
cytoskeletal components in hematopoietic cells
• Because of the absence of this protein, platelets and leukocytes do
not develop normally, are small, and fail to migrate normally
Lymphocyte Abnormalities Associated with Other Diseases

38
• Ataxia-telangiectasia is characterized by gait abnormalities
(ataxia), vascular malformations (telangiectasia), and
immunodeficiency
• The disease is caused by mutations in a gene whose product is
involved in DNA repair
• Defects in this protein lead to abnormal DNA repair (e.g., during
recombination of antigen receptor gene segments), resulting in
defective lymphocyte maturation
Lymphocyte Abnormalities Associated with Other Diseases

39

40
Morimoto Y and Routes JM. 2008. Immunodeficiency Overview. Prim Care Clin Office Pract, 35, 159–173
Approach for The Diagnosis of Primary Immunodeficiency

S e c o n d a r y
I m m u n o d e f i c i e n c i e s
41

42
Secondary Immunodeficiencies
• Deficiencies of the immune system often develop because of
abnormalities that are not genetic but are acquired during life
• The most serious of these abnormalities worldwide is HIV infection
• The most frequent causes of secondary immunodeficiencies in are
cancers involving the bone marrow and various therapies
• Cancer treatment with chemotherapeutic drugs and irradiation may
damage proliferating cells, including bone marrow precursors and
mature lymphocytes, resulting in immunodeficiency
• Immunosuppressive drugs used to prevent graft rejection and
drugs for inflammatory diseases, including some of the newer
therapies (e.g., TNF antagonists, costimulation blockade), are
designed to blunt immune responses

43
Cause Mechanism
Human immunodeficiency virus infection Depletion of CD4+ helper T cells
Irradiation and chemotherapy treatments for
cancer
Decreased bone marrow precursors for all leukocytes
Immunosuppression for graft rejection and
inflammatory diseases
Depletion or functional impairment of lymphocytes
Involvement of bone marrow by cancers
(metastases, leukemias)
Reduced site of leukocyte development
Protein-calorie malnutrition Metabolic derangements inhibit lymphocyte maturation
and function
Removal of spleen Decreased phagocytosis of microbes
Secondary Immunodeficiencies

44
Acquired Immunodeficiency Syndrome
• AIDS is caused by infection with HIV
• 34 million HIV-infected people worldwide, in Africa (70%) and Asia
(20% )
• More than 30 million deaths are attributable to HIV/AIDS
• Human immunodeficiency virus is a retrovirus that infects cells of
the immune system, mainly CD4+ T lymphocytes, and causes
progressive destruction
• Infectious HIV particle consists of two RNA strands within a protein
core, surrounded by a lipid envelope derived from infected host
cells but containing viral proteins
• The viral RNA encodes structural proteins, various enzymes, and
proteins that regulate transcription of viral genes and the viral life
cycle

45
Morphology HIV Virus

46
Life Cycle HIV

47
Abbas AB, et al. 2014. Basic Immunology: Functions
and Disorders of the Immune System. Philadelphia.
Elsevier Inc.
Pathogenesis HIV

Clinical Course of HIV
Disease

Common Features of Late-stage HIV Infection
1. Multiple Kaposi’s sarcoma
lesions on the chest and
abdomen.
2. Chest radiograph of a patient
with Pneumocystis carinii
pneumonia, showing bilateral
interstitial shadowing.
3. Small bowel biopsy from a
patient with diarrhea caused
by cryptosporidia, showing
intermediate forms of
croptosporidia (small pink
dots) on the surface of the
mucosa.
4. Computed tomography scan
of the head of patient with
cerebral toxoplasmosis. The
patient presented with a
history of fits and weakness
of the left arm and leg.
Infection of contrast revealed
a ring-enhancing lesion in the
right hemisphere (arrow),
with surrounding edema
(dark area).

Clinical Features of HIV Infection
Phase of disease Clinical feature
Acute HIV disease Fever, headaches, sore throat with pharyngitis, generalized
lymphadenopathy, rashes
Clinical latency
period
Declining blood CD4+ T cell amount
AIDS Oportunistic infections :
Protozoa (Toxoplasma Cryptosporidium)
Bacteria (Mycobacterium avium, Nocardia, Salmonella)
Fungi (Candida, Cryptococcus neoformans, Coccidioides
immitis, Histoplasma capsulatum, Pneumocystis)
Viruses (cytomegalovirus, herpes simplex, varicella-zoster
Tumors :
Lymphomas (including EBV-associated B cell lymphomas
Kaposi’s sarcoma
Cervical carcinoma
Encephalopathy
Wasting syndrome

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