This document discusses the immunological functions of lymphocytes and their clinical implications. It begins by describing the different types of lymphoid precursor cells including T cells, B cells, natural killer cells, and plasmacytoid dendritic cells. It then discusses T cell and B cell maturation processes and the roles of different T cell and B cell subtypes. Key points covered include T cell stimulation pathways, memory T cell populations, immunoglobulin classes, and the functions of natural killer cells and plasmacytoid dendritic cells. The document concludes by examining disorders of lymphocytes including primary immunodeficiencies affecting T cells and B cells such as SCID, DiGeorge syndrome, and common variable immunodeficiency.

1. IMMUNOLOGICAL FUNTIONS OF
LYMPHOCYTES AND ITS CLINICAL
IMPLICATION
PRESENTER – DR RAHUL CHHABRA
MODERATOR – DR MRITUNJOY ROY

2. THE IMMUNE SYSTEM

3. LYMPHOID PRECURSOR CELLS:
 T CELLS– 80% OF PERIPHERAL BLOOD LYMPHOCYTES
 B CELLS–10-15% OF PERIPHERAL BLOOD LYMPHOCYTES
 NATURAL KILLER CELLS –5-15% OF PERIPHERAL
BLOOD LYMPHOCYTES
 PLASMACYTOID DENTRITIC CELLS.
ADAPTIVE IMMUNITY

4. T CELLS MATURATION :
 PROGENITOR OF T CELLS ARE PRODUCED IN THE BONE MARROW BUT
DEVELOPMENT AND MATURATION OF IMMUNOLOGICALLY COMPETENT T CELLS
OCCUR IN THE THYMUS.
 THE MOST IMPORTANT ENVIROMENTAL CUE FOR T-CELL COMMITMENT IS
DELIVERED BY THE THYMIC EPITHELIUM CELLS IN THE FORM NOTCH
LIGANDS.
 COMMITED T CELLS ENTER THE THYMUS THROUGH HIGH ENDOTHELIAL
VENULE WHICH IS MEDIATED BY PSGL-1(P SELECTIN
GLYCOPROTEIN) WHICH INTERACTS WITH P SELECTIN.

6. T CELL STIMULATION:
 T CELL STIMULATION HAPPENS WITH AN ANTIGEN PRESENTING CELLS.
 T CELL RECEPTOR OF CD4CD8 CELL BINDS WITH MHC CLASS 12 OF ANTIGEN
PRESENTING CELLS
 ALSO A CO-STIMULATORY SIGNAL IS ESSSETIAL FOR ACTIVATION OF T
CELLS.(CD 28 OF T CELL WITH CD8086 OF ANTIGEN PRESENTING CELLS)
 INCREASED CALCIUM INFLUX OCCURS AFTER T CELL ACTIVATION
 CALCIUM BINDS WITH CAL MODULIN COMPLEX WHICH FURTHER ACTIVATES
CALCINEURIN( IS A PHOSPHATASE ENZYME)
 CALCINEURIN ACTIVATES NFAT(NUCLEAR FACTOR OF ACTIVATED T CELLS) BY
DEPHOSPHORYLATION AND LEADING TO PRODUCTION OF INTERLUKIN 2
MOLECULES(IL2)
 IL2 BINDS WITH IL2 RECEPTOR ON T CELLS WHICH LEADS TO ACTIVATION OF
P13K-AKT-MTOR PATHWAY AND BCL2 IS INCREASED.
 THUS ACTIVATING CELL CYCLE AND LEADING TO CLONAL PROLIFERATION OF
T CELLS.

7. T CELL SUBTYPES
T Helper 1 cell
Clinical implication :
1. In infections with
intracellular organisms
like mycobacteria

8. T Helper 2 cell
Clinical imiplication
1. Against parasitic
infections
2. Type 1 hypersensitivity
reaction

9. T Helper 17 cell
Clinical implication:
1. Recruit neutrophils to
the skin and lungs to
fight bacterial and fungal
infections
2.Rheumatoid arthritis
3.Psoriasis
4.HyperIgE
syndrome(JOB syndrome)

10. Follicular T Helper cells
Clinical implications
B cell maturation in
Germinal center.

11. T Regulatory cells
Clinical implication:
Downregulation of T
cell function and
prevention of
autoimmunity.

13. MEMORY T CELLS
 TWO POPULATIONS OF LONG LIVED MEMORY T CELLS ARE
TRIGERRED BY INFECTIONS:
 EFFECTOR MEMORY T CELLS : RESIDE IN NON LYMPHOID
ORGANS AND RESPOND RAPIDLY TO REPEATED INFECTIONS
WITH CYTOKINE PRODUCTION AND CYTOTOXIC FUNTIONS TO
KILL VIRUS INFECTED CELLS
 CENTRAL MEMORY T CELLS: RESIDE IN LYMPHOID ORGAN
WHERE THEY REPLINISH LONG AND SHORT LIVED MEMORY T
CELLS AND EFFECTOR MEMORY T CELLS

14. B CELL MATURATION:

15. …CONTD
 Unlike T cells, which recognize only processed peptide fragments of conventional
antigens embedded in the notches of MHC class I and class II antigens of APCs, B
cells are capable of recognizing and proliferating to whole unprocessed native
antigens via antigen binding to B cell–surface Ig (sIg) receptors.
 The primary function of B cells is to produce antibodies. B cells also serve as APCs
and are highly efficient at antigen processing.
 B lymphocyte development can be separated into antigen independent and antigen-
dependent phases.
 Antigen-independent B cell development occurs in primary lymphoid organs and
includes all stages of B cell maturation up to the surface Ig+ mature B cell.
 Antigen dependent B cell maturation is driven by the interaction of antigen with the
mature B cell sIg, leading to memory B cell induction, Ig class switching, and plasma
cell formation.
 After leaving the bone marrow, B cells populate peripheral B cell sites, such as lymph
node and spleen, and await contact with foreign antigens that react with each B cell’s
clonotypic receptor.
 Lymphocytes that synthesize IgG, IgA, and IgE are derived from sIgM+, sIgD+ mature
B cells. Pairs of CD40+B cells and CD40 ligand+ T cells bind and drive B cell Ig class
switching via T cell-produced cytokines such as IL-4 and TGF-b.

16. IMMUNOGLOBULINS:
 The primary functions of antibodies are to bind specifically to antigen and bring about the
inactivation or removal of the offending toxin, microbe, parasite, or other foreign
substance from the body.
 All immunoglobulins have the basic structure of two heavy and two light chains.
 Immunoglobulin isotype (i.e., G, M, A, D, E) is determined by the type of Ig heavy chain
present
 IgG and IgA isotypes can be divided further into subclasses (G1, G2, G3, G4, and A1,
A2).

17. …contd
 1. IgG:
 IgG constitutes ~75–85% of total serum immunoglobulin.
 The four IgG subclasses are numbered in order of their level in serum, IgG1
being found in greatest amounts and IgG4 the least.
 IgG subclasses have clinical relevance in their varying ability to bind
macrophage and neutrophil Fc receptors and to activate complement.
 IgG antibodies are frequently the predominant antibody made after rechallenge
of the host with antigen (secondary antibody response).
 2. IgM:
 IgM antibodies normally circulate as a 950-kDa pentamer with 160-kDa bivalent
monomers joined by a molecule called the J chain.
 IgM is the first immunoglobulin to appear in the immune response (primary
antibody response) and is the initial type of antibody made by neonates.
 Membrane IgM in the monomeric form also functions as a major antigen
receptor on the surface of mature B cells.
 IgM is an important component of immune complexes in autoimmune diseases.

18. …contd
 3.IgA:
 IgA constitutes only 7–15% of total serum immunoglobulin but is the
predominant class of immunoglobulin in secretions.
 IgA in secretions(tears, saliva, nasal secretions, gastrointestinal tract fluid, and
human milk) is in the form of secretory IgA (sIgA), a polymer consisting of two
IgA monomers, a joining molecule, again termed the J chain, and a glycoprotein
called the secretory protein.
 Secretory IgA is produced in amounts of >50 mg/kg of body weight per 24 h
and functions to inhibit bacterial adhesion, inhibit macromolecule
absorption in the gut, neutralize viruses, and enhance antigen elimination
in tissue through binding to IgA and receptor-mediated transport of immune
complexes through epithelial cells.
 IgA1 is primarily found in serum, whereas IgA2 is more prevalent in secretions.
 IgA fixes complement via the alternative complement pathway and has potent
antiviral activity in humans by prevention of virus binding to respiratory and
gastrointestinal epithelial cells.
 4.IgD:
 IgD is found in minute quantities in serum and, together with IgM, is a major
receptor for antigen on the naïve B cell surface.
 5. IgE: IgE, which is present in serum in very low concentrations, is the major
class of immunoglobulin involved in arming mast cells and basophils by binding
to these cells via the Fc region.

19. Natural Killer
Cells
 Large Granular Lymphocytes or natural killer cells account for ~5–15% of peripheral blood
lymphocytes.
 NK cells are nonadherent, nonphagocytic cells with large azurophilic cytoplasmic granules.
 NK cells express surface receptors for the Fc portion of IgG (FcR) (CD16) and for NCAM-I (CD56), and
many NK cells express T lineage markers, particularly CD8.
 NK cells arise in both bone marrow and thymic microenvironments.
 Funtion: Kill foreign and host cells that have low levels of MHC+ self-peptides. Express NK receptors that
inhibit NK function in the presence of high expression of self-MHC.
 Some NK cells express CD3 and invariant TCR-a chains and are termed NK T cells.
 TCRs of NK T cells recognize lipid molecules of intracellular bacteria.
 Upon activation, NK T cells secrete effector cytokines such as IL-4 and IFN-g.
 This mode of recognition of intracellular bacteria such as Listeria monocytogenes and Mycobacterium tuberculosis
helps to kill host cells infected with such organisms.
Plasmacytoid Dendritic Cells
 Produce large amounts of interferon-alpha (IFN-a).
 Plasmacytoid DCs are inefficient APCs.
 IFN-a that activates NK cell killing of pathogen infected cells; IFN-a also activates T cells to mature into
antipathogen cytotoxic (killer) T cells..
Natural killer T cells

20. DISORDERS OF LYMPHOCYTES
A.DEFICIENCIES OF THE ADAPTIVE IMMUNE SYSTEM:
1.Primary disorders:
 T lymphocytes:
 - Impaired development
 Severe combined immune deficiencies(SCIDs)
 DiGeorge’s syndrome
 Impaired survival, migration function
 Combined immunodeficiencies
 Hyper-IgE syndrome (autosomal dominant)
 DOCK8 deficiency
 CD40 ligand deficiency
 Wiskott-Aldrich syndrome
 Ataxia-telangiectasia and other DNA repair deficiencies

21. …CONT
 • B lymphocytes:
 - Impaired development
 XL And AR agammaglobulinemia
 Impaired function:
 Hyper-IgM syndrome
 Common variable immunodeficiency(CVID)
 IgA deficiency

22. T LYMPHOCYTE DEFICIENCIES
 T CELL DEFICIENCIES ACCOUNT FOR 20% OF ALL PRIMARY IMMUNE
DEFICIENCIES.
 GIVEN THE CENTRAL ROLE OF T LYMPHOCYTES IN ADAPTIVE IMMUNE RESPONSE
PID’S INVOLVING T CELL DEFICIENCIESHAVE SEVERE PATHOLOGICAL
CONSEQUENCES AND POOR PROGNOSIS.
1.SEVRE COMBINED IMMUNODEFICIENCIES

23.  SCIDs constitute a group of rare PIDs characterized by a profound block in
T cell development and thus the complete absence of these cells.
 The developmental block is always the consequence of an intrinsic
deficiency.
 Incidence of SCID is estimated to be 1 in 50,000 live births.
 CLINCAL MANIFESTATIONS:
 Given the severity of the T cell deficiency, clinical consequences
occur early in life (usually within 3 to 6 months of birth).
 The most frequent clinical manifestations are recurrent oral
candidiasis, failure to thrive, and protracted diarrhea and/or acute
interstitial pneumonitis caused by Pneumocystis jiroveci.
 Severe viral infections or invasive bacterial infections can also occur
 Patients may also experience complications related to infections
caused by live vaccines
 bacille Calmette-Guérin [BCG] vaccine may lead not only to local
and regional infection but also to disseminated infection manifested
by fever, splenomegaly, and skin and lytic bone lesions

24. ..cont
 Diagnosis:
 diagnosis of SCID can be suspected based on the patient’s clinical history
and, possibly, a family history of deaths in very young children (suggestive
of either X-linked or recessive inheritance).
 Lymphocytopenia is strongly suggestive of SCID in >90% of cases.
 The absence of a thymic shadow on a chest x-ray can also be suggestive
of SCID.
 An accurate diagnosis relies on precise determination of the number of
circulating T, B, and NK lymphocytes and their subsets.
 T cell lymphopenia may be masked in some patients by the presence of
maternal T cells.
 Inheritance pattern analysis and lymphocyte phenotyping can discriminate
between various forms of SCID.
 T cell quantification of receptor excision circles (TREC) by using the
Guthrie card is a reliable diagnostic test for newborn screening

25. .cont
 5 distinctive causative mechanism for SCID have been identified:
 1. SEVERE COMBINED IMMUNODEFICIENCY CAUSED BY A CYTOKINE-
SIGNALING DEFICIENCY:
 most frequent SCID phenotype(40–50% of all cases)
 absence of both T and NK cells deficiency in either the common g chain (gc) receptor
that is shared by several cytokine receptors (the IL-2, 4, 7, 9, 15, and 21 receptors) or
Jak-associated kinase (JAK) 3 that binds to the cytoplasmic portion of the gc chain
receptor and induces signal transduction following cytokine binding.
 gc deficiency has an X-linked inheritance mode while JAK 3 deficiency is autosomal
recessive.
2. PURINE METABOLISM DEFICIENCY 10 to 20% of SCID patients exhibit a deficiency
in adenosine deaminase (ADA).
 ADA an enzyme of purine metabolism that deaminates adenosine (ado) and
deoxyadenosine(dAdo).
 Results in the accumulation of ado and dAdo metabolites that induce premature cell
death of lymphocyte progenitor cells.
 results in the absence of B and NK lymphocytes as well as T cells
 Clinical expression of complete ADA deficiency typically occurs very early in life.
Since ADA is a ubiquitous enzyme, its deficiency can also cause bone dysplasia with
abnormal costochondral junctions and metaphyses (found in 50% of cases) and
neurologic defects.

26. …CONTD
 3. DEFECTIVE REARRANGEMENTS OF T AND B CELL RECEPTORS
 autosomal recessive inheritance and account for 20–30% of SCID cases.
 mutations in genes encoding proteins that mediate the recombination of V(D)J gene
elements in T and B cell antigen receptor genes.
4. DEFECTIVE (PRE-)T CELL RECEPTOR SIGNALING IN THE THYMUS
 Caused by a series of rare deficiencies in molecules involved in signaling via the pre-
TCR or the TCR. These include deficiencies in CD3 subunits associated with the (pre-
)TCR and CD45.
 5. RETICULAR DYSGENESIS
 extremely rare T and NK cells deficiency with severe neutropenia and sensorineural
deafness. It results from an adenylate kinase 2 deficiency.
 Treatment and management of SCID:
 aggressive anti infective therapies, immunoglobulin replacement, and (when
necessary) parenteral nutrition support.
 HSCT provides a very high curative potential for SCID patients.
 The treatment of ADA deficiency consists of enzyme substitution with a pegylated
enzyme.

27. DiGeorge’s syndrome
 A profound T cell defect can also result from faulty development of the thymus. i.e abnormal
cephalic neural crest cell migration and differentiation in the third and fourth pharyngeal arches
during early embryonic development.
 Vast majority of patients with DGS have partial monosomy of human chromosome 22q11.2
diagnosed on immunofluorescence in situ hybridisation.
• Clinical phenotype of DGS consists of the triad of 1. congenital cardiac defects, 2. hypocalcemia
as a result of parathyroid insufficiency, and immune deficiency as a consequence of aplasia or
hypoplasia of the thymus. CATCH 22 [Cardiac abnormality (commonly interrupted aortic
arch, truncus arteriosus and tetralogy of Fallot) Abnormal facies Thymic aplasia Cleft palate
Hypocalcemia/hypoparathyroidism]
 Most patients have residual thymic tissue and hence mild to moderate T-cell lymphopenia
 Approximately 1 percent of DGS patients lack T cells completely, resembling SCID .
 Treatment :Cardiovascular anomalies require prompt attention and hypocalcemia appropriate
medical treatment.
 Depending on the extent of the immune deficiency, patients may require antibiotic prophylaxis or
IVIG therapy. Patients with complete DGS require more aggressive treatment. Allogenic thymic
transplantation may restore T-cell development and function in approximately 75 percent of these
patients.
 CHARGE (coloboma of the eye, heart anomaly, choanal atresia, retardation, genital, and ear
anomalies) syndrome (CHD7 deficiency) is a less frequent cause of impaired thymus
development.

28. OMENN SYNDROME
 Omenn syndrome consists of a subset of T cell deficiencies present with early
onset erythrodermia, alopecia, hepatosplenomegaly, and failure to thrive.
 Hypomorphic mutations in genes usually associated with SCID, that is, RAG-
1, RAG-2, or (less frequently) ARTEMIS or IL-7R. Thymic expression of AIRE
(autoimmune regulator), a transcription factor involved in presentation of self-
antigens and negative selection of autoreactive thymocytes, is reduced.
 patients usually display T cell lymphocytosis, eosinophilia, and low B cell
counts. serum IgE is often elevated.
 Differential diagnosis includes maternal T-cell engraftment in patients with
SCID, complete atypical DiGeorge syndrome, CHARGE syndrome
 These patients are very fragile,requiring simultaneous anti-infective therapy,
nutritional support, and immunosuppression. HSCT provides a curative
approach.

29. Functional T Cell Defects
 A subset of T cell PIDs with autosomal inheritance characterized by partially
preserved T cell differentiation but defective activation resulting in abnormal
effector function.
 lead to susceptibility to viral and opportunistic infections, chronic diarrhea,
and failure to thrive, with onset during childhood.
 1. ZETA-ASSOCIATED PROTEIN 70 (ZAP70) DEFICIENCY
 Zeta-associated protein 70 (ZAP70) is recruited to the TCR following antigen
recognition.
 A ZAP70 deficiency leads typically to an almost complete absence of CD8+ T
cells.
 CD4+ T cells are present but cannot be activated.
 2. CALCIUM SIGNALING DEFECTS
 Profound defect in in vitro T and B cell activation as a result of defective
antigen receptor-mediated Ca2+ influx.
 defect is caused by a mutation in the calcium channel gene (ORAI1) or its
activator (STIM-1).

30. …contd
 3. HUMAN LEUKOCYTE ANTIGEN (HLA) CLASS II DEFICIENCY
 A group of four recessive genetic defects all of which affect molecules (RFX5,
RFXAP, RFXANK, and CIITA) involved in the activation of the genes coding
for HLA class II.
 As a result, low but variable CD4+ T cell counts are observed in addition to
defective antigen-specific T and B cell responses.
 patients are particularly susceptible to herpesvirus, adenovirus, and
enterovirus infections and chronic gut/liver Cryptosporidium infections.
 4. HLA CLASS I DEFICIENCY
 Defective expression of molecules involved in antigen presentation by HLA
class I molecules(TAP-1, TAP-2, and Tapasin) leading to reduced CD8+ T cell
counts, loss of HLA class I antigen expression, and a particular phenotype
consisting of chronic obstructive pulmonary disease and severe vasculitis.

31. T Cell Primary Immunodeficiencies with DNA
Repair
Defects
Combination of T and B cell defects of variable intensity.
 1. Ataxia-telangiectasia
 Autosomal recessive disorder ataxia-telangiectasia (AT) is the most frequently encountered condition in
this group.
 incidence of 1:40,000 live births and causes B cell defects (low IgA, IgG2 deficiency, and low antibody
production), which often require immunoglobulin replacement.
 AT is associated with a progressive T cell immunodeficiency
 AT is caused by a mutation in the gene encoding the ATM protein—a kinase that plays an important role
in the detection and repair of DNA lesions
 hallmark features of AT are telangiectasia and cerebellar ataxia.
 Diagnosis is based on a cytogenetic analysis showing excessive chromosomal rearrangements (mostly
affecting chromosomes 7 and 14) in lymphocytes.
 2.Nijmegen breakage syndrome (NBS)
 less common condition that also results from chromosome instability
 characterized by a severe T and B cell combined immune deficiency with autosomal recessive
inheritance . NBS results from a deficiency in nibrin (NBSI, a protein associated
 with MRE11 and Rad50 that is involved in checking DNA lesions).
 Patients exhibit microcephaly and a bird-like face, but have neither ataxia nor telangiectasia

32. …CONTD
 3. Dyskeratosis congenita (also known as Hoyeraal- Hreidarsson
syndrome)
 progressive immunodeficiency that can also include an absence of B and NK
lymphocytes, progressive bone marrow failure, microcephaly, in utero growth
retardation, and gastrointestinal disease.
 disease can be X-linked or, more rarely, autosomal recessive.
 mutation of genes encoding telomere maintenance proteins, including
dyskerin (DKC1).
 4. Immunodeficiency with centromeric and facial anomalies (ICF)
 complex syndrome of autosomal recessive inheritance that variably combines
a mild T cell immune deficiency with a more severe B cell immune
deficiency
 coarse face, digestive disease, and mild mental retardation.
 A diagnostic feature is the detection by cytogenetic analysis of multiradial
aspects in multiple chromosomes (most frequently 1, 9, and 16)
corresponding to an abnormal DNA structure secondary to defective DNA
methylation.

33. T Cell Primary Immunodeficiencies with Hyper-
IgE
 Several T cell PIDs are associated with elevated serum IgE levels.
 1. Autosomal recessive hyper-IgE syndrome
 Is notably characterized by recurrent bacterial infections in the skin and respiratory
tract and severe skin and mucosal infections by pox viruses and human
papillomaviruses, together with severe allergic manifestations.
 T and B lymphocyte counts are low.
 Mutations in the DOCK8 gene have been found
 2. Autosomal Dominant Hyper-IgE Syndrome
 Clinical features: recurrent skin and lung infections that can be complicated by
pneumatoceles. facial dysmorphy, defective loss of primary teeth,hyperextensibility,
scoliosis, and osteoporosis.
 Elevated serum IgE levels are typical of this syndrome.
 This condition is caused by a heterozygous (dominant) mutation in the gene encoding
the transcription factor STAT3 that is required in a number of signaling pathways
following binding of cytokine to cytokine receptors.
 Also partially defective antibody production because of defective IL-21R signaling.
 Treatment : immunoglobulin substitution can be considered as prophylaxis of bacterial
infections.

34. Wiskott-Aldrich Syndrome:
 WAS is a complex X-linked disease
 Incidence of ~1 in 200,000 live births
 mutations in the WASP gene that affect not only T lymphocytes but also the
other lymphocyte subsets, dendritic cells, and platelets.
 Clinical manifestations: recurrent bacterial infections, eczema, and bleeding
caused by thrombocytopenia .
 Invasive and bronchopulmonary infections, viral infections, severe eczema,
and autoimmune manifestations like autoantibody-mediated blood cytopenia,
glomerulonephritis, skin and visceral vasculitis (including brain vasculitis),
erythema nodosum, and arthritis.
 Another possible consequence of WAS is lymphoma, which may be virally
induced (e.g., by EBV or Kaposi’s sarcoma–associated herpesvirus).
 Thrombocytopenia can be severe and compounded by the peripheral
destruction of platelets associated with autoimmune disorders.
 The immunologic workup is not very informative; there can be a relative CD8+ T
cell deficiency, frequently accompanied by low serum IgM levels and decreased
antigen-specific antibody responses. A typical feature is reduced-sized platelets
on a blood smear

35. …contd
 Diagnosis is based on intracellular immunofluorescence analysis of WAS protein
 (WASp) expression in blood cells.
 The treatment of WAS should match the severity of disease expression. Prophylactic
 antibiotics, immunoglobulin G (IgG) supplementation, and careful topical treatment of
eczema are indicated.
 Although splenectomy improves platelet count in a majority of cases, this intervention is
associated with a significant risk of infection (both before and after HSCT). Allogeneic
HSCT is curative, with fairly good results overall.

36. B LYMPHOCYTE
DEFICIENCIES
 Deficiencies that predominantly affect B lymphocytes are the most frequent
PIDs and account for 60–70% of all cases.
 Defective antibody production therefore allows the establishment of invasive,
pyogenic bacterial infections as well as recurrent sinus and pulmonary
infections (mostly caused by Streptococcus pneumoniae, Haemophilus
influenzae, Moraxella catarrhalis, and, less frequently, gram-negative
bacteria).
 Recurrent bronchial infections lead to bronchiectasis and, ultimately, cor
pulmonale and death.
 Parasitic infections such as caused by Giardia lamblia and bacterial
infections caused by Helicobacter and Campylobacter of the gut are also
observed.
 most profound of B cell deficiencies, infections rarely occur before the age of
6 months; this is because of transient protection provided by the
transplacental passage of immunoglobulins during the last trimester of
pregnancy.
 Diagnosis of B cell PIDs relies on the determination of serum Ig levels .
 Another useful test is B cell phenotype determination in switched μ−d−
CD27+ and nonswitched memory B cells (μ+d+ CD27+).

37. B LYMPHOCYTE DEFICIENCIES:

38. Agammaglobulinemia
 Agammaglobulinemia is characterized by a profound defect in B cell
development (<1% of the normal B cell blood count).
 85% of cases, agammaglobulinemia is caused by a mutation in the BTK
gene that is located on the X chromosome.
 BTK gene product is a kinase that participates in (pre) B cell receptor
signaling. When the kinase is defective, there is a block at the pre-B to B cell
stage.
 Diagnosis: Detection of BTK by intracellular immunofluorescence of
monocytes is a useful diagnostic test.
 10% of agammaglobulinemia cases are caused by alterations in genes
encoding elements of the pre-B cell receptor, i.e., the μ heavy chain, the
l5 surrogate light chain, Iga or Igb, the scaffold protein BLNK, and the p85
alpha subunit of phosphatidylinositol 3 phosphate kinase (P13K) and the
Ikaros transcription factor.
 In 5% of cases, the defect is unknown.
 Treatment of agammaglobulinemic patients is based on immunoglobulin
replacement.

39. Hyper-IgM (HIGM)
Syndromes
 HIGM is a rare B cell PID characterized by defective Ig CSR(class switch recombination)
It results in very low serum levels of IgG and IgA and elevated or normal serum IgM levels.
 The clinical severity is similar to that seen in agammaglobulinemia , although chronic lung
disease and sinusitis are less frequent and enteroviral infections are uncommon.
 Diagnosis of HIGM involves screening for an X-linked CD40L deficiency and an autosomal
recessive CD40 deficiency, which affect both B and T cells.
 IgM-mediated autoimmunity and lymphomas can occur in HIGM syndrome.
 HIGM can result from fetal rubella syndrome.
Common Variable Immunodeficiency
 Condition characterized by low serum levels of one or more Ig isotypes.
 Its prevalence is estimated to be 1 in 20,000 , 10% have a family history.
 Recognized predominantly in adults, although clinical manifestations can occur earlier in
life.
 B cells do not convert to plasma cells thus hypogammaglobinemias.
 B lymphocyte counts are often normal but can be low.
 CVID patients may develop lymphoproliferation (splenomegaly), granulomatous lesions,
colitis, antibody-mediated autoimmune disease, and lymphomas

40. …contd
 The B-cell activating factor (BAFF) receptor was found to be defective in patients
with CVID.
 In 10% of patients with CVID, monoallelic or biallelic mutations of the gene
encoding TACI (a member of the tumor necrosis factor [TNF] receptor family that
is expressed on B cells) have been found.
Selective Ig Isotype Deficiencies
 IgA deficiency is the most common PID
 found in 1 in every 600 individuals
 It is asymptomatic in most cases
 Individuals may present with increased numbers of acute and chronic respiratory
infections that may lead to bronchiectasis.
 Increased susceptibility to drug allergies, atopic disorders, and autoimmune
diseases.
 IgA deficiency may progress to CVID

41. Immunoglobulin replacement
 IgG antibodies have a half life of 21–28 days.
 Thus, injection of plasma-derived polyclonal IgG containing a myriad of high-affinity
antibodies can provide protection against disease-causing microorganisms in
patients with defective IgG antibody production.
 Immunoglobulin replacement can be performed by IV or subcutaneous routes.
 Injections have to be repeated every 3–4 weeks, with a residual target level of 800
mg/mL.
 Subcutaneous injections are typically performed once a week, although the
frequency can be adjusted on a case-by-case basis.
 In patients with chronic lung disease, chest physical therapy with good pulmonary toilet and
the cyclic use of antibiotics are also needed.

42. PRIMARY IMMUNODEFICIENCIES
AFFECTING REGULATORY PATHWAYS
A. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
 Characterized by an uncontrolled activation of CD8+ T lymphocytes and macrophages that leads to
organ damage (notably in the liver, bone marrow, and central nervous system).
 The manifestations of HLH are often induced by a viral infection. EBV is the most frequent trigger.
 Disease onset may start during the first year of life or even (in rare cases) at birth.
 Diagnosis based on characteristic symptoms : fever, hepatosplenomegaly, edema, neurologic
diseases, blood cytopenia, increased liver enzymes, high triglyceride levels, elevated markers of T
cell activation, and hemophagocytic features in the bone marrow or cerebrospinal fluid.
 Classified into 3 subsets:
 1. Familial HLH with autosomal recessive inheritance:including perforin deficiency (30% of
cases) that can be recognized by assessing intracellular perforin expression.
 2. HLH with partial albinism.
 3. X-linked lymphoproliferative disease (XLP)
 characterized in most patients by the induction of HLH following EBV infection.
 Several immunologic abnormalities have been described like NK cell cytotoxicity, impaired
differentiation of NKT cells, defective antigen-induced T cell death, and defective T cell helper activity
for B cells.

43. …contd
 HLH is a life-threatening complication.
 The treatment equires aggressive immunosuppression with either the cytotoxic agent
etoposide or anti–T cell antibodies.
B. AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME:
 The syndrome is caused by a defect in Fas mediated apoptosis of lymphocytes.
 Characterized by nonmalignant T and B lymphoproliferation causing splenomegaly and
enlarged lymph nodes.
 70% of patients also display autoimmune manifestations such as autoimmune cytopenias,
Guillain-Barré syndrome, uveitis, and hepatitis.
 Hallmark: presence of CD4–CD8– TCRab+ T cells (2–50%) in the blood of affected
individuals.
 Hypergammaglobulinemia involving IgG and IgA.
 Treatment of ALPS is essentially based on the use of proapoptotic drugs.
C. Immunodysregulation polyendocrinopathy enteropathy X-linked
syndrome (IPEX):
 Caused by loss-of-function mutations in the gene encoding the transcription factor FOXP3,
which is required for the acquisition of effector function by regulatory T cells.

44. …contd
 Characterized by a widespread inflammatory enteropathy, food intolerance, skin
rashes, autoimmune cytopenias, and diabetes.
 This condition has a poor prognosis and requires aggressive immunosuppression.
 The only possible curative approach is allogeneic HSCT.
 4. Autoimmune polyendocrinopathy candidiasis ectodermal
dysplasia (APECED) syndrome:
 autosomal recessive inheritance.
 Multiple autoimmune manifestations that can affect solid organs in general and
endocrine glands in particular.
 Mild, chronic Candida infection is often associated.
 The condition is due to mutations in the autoimmune regulator (AIRE) gene and
results in impaired thymic expression of self-antigens by medullary epithelial cells
and impaired negative selection of self-reactive T cells that leads to autoimmune
manifestations.

45. A.DEFICIENCIES OF THE ADAPTIVE IMMUNE
SYSTEM:
2.Acquired disorders:
 A. Aplastic anemia
 B. Infectious diseases
 1. Viral diseases
a. Acquired immunodeficiency syndrome.
b. Severe acute respiratory syndrome.
c. West Nile encephalitis.
d. Hepatitis.
e. Influenza.
f. Herpes simplex virus.
g. Herpes virus type 6 (HHV-6).
h. Herpes virus type 8 (HHV-8).
i. Measles virus.
 2. Bacterial diseases
a. Tuberculosis
b. Typhoid fever
c. Pneumonia
d. Rickettsiosis
e. Sepsis
 3. Parasitic diseases
a. Acute phase of malaria infection
 C. Iatrogenic
 1. Immunosuppressive agents
a. Antilymphocyte globulin therapy,
b. Alemtuzumab .
c. Glucocorticoid

46. …contd
 2. High-dose psoralen plus ultraviolet A treatment
3. Stevens-Johnson syndrome.
4. Chemotherapy
5. Renal transplant
6. Radiation
7. Major surgery
8. Extracorporeal bypass circulation
9. Hematopoietic stem cell transplant
10. Thoracic duct drainage.
11. Hemodialysis.
12. Pheresis for donor lymphocyte infusion.
 E. Nutritional and dietary
1. Ethanol abuse
2. Zinc deficiency
 III. Idiopathic
A. Idiopathic CD4+ T lymphocytopenia

47. Thank you