Lecture 18: Failures of Host Defense Mechanisms

Types of immunodeficiencies

Primary immunodeficiencies

secondary immunodeficiencies

combined immunodeficiencies

Primary Immunodeficiencies

• PIDS (or congenital) are a heterogenous group of inherited disorders with defects (genetic mutations) in one or more components of the immune system

• PIDs are not as rare as once believed

• Infections are hallmarks

Secondary Immunodeficiencies

• Non-inherited, acquired

• caused by environmental factors such as malnutrition, age, infection, irradiation, chemotherapy, or exposure to toxins

• infections are hallmarks

combined immunodeficiencies

• impairments in both B-cell and T-cell function due to inherited mutations

what are primary immunodeficiencies caused by

caused by inherited gene variants that typically cause recurrent infections in early life

pyogenic, or pus-forming, bacteria →

a defect in antibody, complement, or phagocyte function

persistent fungal or viral infection→

defect in T-cell function

how many people are affected by primary immunodeficiencies

1 in 1000 people in the US - 80% of people are <20 yo

how are primary immunodeficiencies often inherited

often inherited in X-linked recessive manner - 70% cases among males

human immunodeficiency syndromes how many categories

9 categories

decreased T cells →

viral/fungal susceptibility

decreased B cells →

pyogenic bacterial infections

decreased phagocytes

abscess formation, catalase + infections

decreased complement

Neisseria infections

SCIDs linked to what

T-cell and B-cell Development

what is SCID

the most severe form of primary immunodeficiency

what is SCID characterized by

defective T-cell development, with secondary impairment of B and NK cells

how does SCID present

in the first months of life: failure to thrive, chronic diarrhea, oral thrush, persistent viral or fungal infections

is SCID fatal

fatal if untreated; curable by hematopoietic stem cell transplantation (HSCT) or gene therapy

Autosomal recessive SCID

Adenosine deaminase (ADA) deficiency → disrupts S-phase of cell cycle → improper lymphocyte development → lack of circulating T and B cells

causes SCID in infancy - must be treated with bone marrow transplantation

Omenn Syndrome

partial loss of V(D)J recombinase activity through mutations in at least one of the RAG1 or RAG2 alleles

peripheral T cells are autoreactive

Autosomal recessive SCID - both boys and girls are affected

X-linked SCID

X-chromosome recessive inherited immunodeficiency that presents with virtual lack of peripheral blood T cells and NK cells. B cells are usually present but Ig production is reduced

what is X-linked SCID caused by

caused by mutation of the IL-2RG, the gene encoding the IL common gamma chain (gc) of the cytokine receptors for IL-2, -4, -7, -9, -15, and -21

what percent of cases of SCID does X-linked SCID account for

incidence of ~1:100,000 male births - accounts for approx half the cases of SCID

in normal cytokine signaling, yc pairs with what

specific ab receptor chains → JAK1/JAK3 → STAT activation → lymphocyte development and proliferation

in IL2RG mutated cells, what happens to these pathways

these pathways are nonfunctional:

• IL-7/IL-7Ryc → required for T-cell differentiation in thymus

• IL-15/IL-15Ryc → required for NK-cell differentiation

immunodeficiencies that alter T-cell development and function

FOXN1 mutation

DiGeorge syndrome

Bare Lymphocyte syndrome

FOXN1 mutation

lack of thymic function - abnormal T cell development

DiGeorge syndrome

22q11.2 deletion

small portion of ch22 deleted

thymus is absent - abnormal T-cell development and function

very difficult to treat

Bare Lymphocyte Syndrome (BLS)

MHC Class II deficiency or MHC Class I deficiency

mutations in TAP genes - improper activation of CD8 T cells (MHC class I deficiency)

mutation in transcription factors responsible for MHC class II expression - improper activation of CD4 T cells (MHC Class II deficiency)

Immunodeficiencies that alter B-cell development

X-linked Agammaglobulinemia (XLA)

Hyper IgM syndrome

Common Variable (CVID)

X-linked Agammaglobulinemia (XLA)

• failure of B-cell precursors to mature into B cells and then plasma cells

• Mutation in BTK gene located on C chromosome

• BTK transmits signal from pre-BCR necessary for maturation beyond pre-B stage

• without BTK signalling, B-cell development arrests in the bone marrow → no mature B cells or plasma cells

• low levels of all isotypes

• reduced B cell numbers

Hyper IgM syndrome

• caused by mutation in the CD40 ligand gene

• CD40L expressed on activated CD4+ T cells

• Affects Igs and impacts only males

• low levels of serum Igs

• IgG, IgA, IgE are low

• IgM may be low, normal, or elevated

• heightened susceptibility to infections that require high-affinity, class-switched antibodies for clearance

Common Variable (CVID)

most common form of PID

variable deficiencies in 2 or more Ig isotypes

low IgG and IgA, with or without low IgM

defective B-cell activation and plasma-cell differentiation despote normal numbers of mature B cells

Defects in the complement system

account for ~2-5% of PIDs

a. Classical pathway (C1q, C1r/s, C2, C4)

activates via ag-antibody complexes

deficiency phenotype:

• failure to clear immune complexes → lupus-like autoimmunity

• recurrent sinopulmonary infections (streptococcus, Haemophilus)

B. mannose-binding lectin pathway

triggered by lectin recognition of microbial carbohydrates

Deficiency (MBL, MASP-1, MASP-2)

• common in children (~5-10% population heterozygous)

• usually mild → recurrent bacterial infections in infancy/childhood, esp respiratory

• often subclinical in adults

c. Alternative pathway (Factor D, Factor P, Properdin)

provides constant surveillance (“tick-over”

Deficiency:

• reduced opsonization of encapsulated bacteria

• predisposes Neisseria and pyogenic infections, but not to immune complex disease (since no immune complex clearance role)

Immunodeficiencies of innate immune system

Chronic Granulomatous Disorder (CGD)

Leukocyte Adhesion Deficiency (LAD) I

Chediak-Higashi Syndrome

Chronic Granulomatous Disorder (CGD)

• caused by defects in phagocytes

• phagocytic cells cannot kill certain pathogens → form granulomas

• defective production of ROS needed for killin

• patients vulnerable to severe recurrent bacterial and fungal infections

Leukocyte Adhesion Deficiency (LAD) I

defects in migration of phagocytes

• reduced or absent expression of B2 integrins on leukocytes

• patients deficient in expression of the 3 integrins containing CD18 (LFA-1 (CD11a/CD18) MAC-1 (CD11b/CD18), Gp 150/95 (CD11c/CD18)

Chediak-Higashi Syndrome

• defects in phagocytes

• impaired lysis of phagocytosed bacteria → recurrent bacterial respiratory and other infections and oculocutaneous albinism

• mutation in CHS gene → affects synthesis of storage/secretory granules in various immune cells

• abnormal NK cell function

• defective lysosomal function in macrophages, DCs and neutrophils

• hypopigmentation of skin, eye, and hair

Evasion of the Host Immune System

Mechanism of Immune Evasion - Genetic Variation

Antigenic drift and antigenic shift

antigenic variation

• pathogen express different surface antigens without changing the bacterial genus and species

• indeed, many species have multiple, serotypes, which differ on their surface and thus are not recognized by the same immunoglobulins

• vaccines target multiple capsule types to broaden coverage

antigenic drift

Accumulation of point mutations during viral RNA replication (error-prone RNA polymerase)

• gradual changes in hemagglutinin (HA) or neuraminidase (NA) epitopes

• occurs continually → leads to seasonal influenza epidemics

• pre-existing antibodies become partially ineffective

Antigenic Shift

Reassortment of viral genome segments between human and animal influenza strains in a co-infected host (e.g. pig, bird)

• produces novel HA or NA combinations that are entirely new to human immunity

• responsible for pandemics (H1N1, H2N2)

Viral Latency

state of nonproductive infection where the viral genome persists in host cells but no new virions are produced → allows lifelong persistence without continuous immune activation

The HSV step 1: primary infection

• HSV-1 (oral) or HSV-2 (genital) infects epithelial cells at the mucosal surface

• viral replication produces vesicular lesions and triggers a strong adaptive immune response

• virus then enters sensory nerve endings and travels retrograde to the trigeminal (or sacral) ganglion

Step 2: latent phase

• viral genome maintained as episomal DNA within neuronal nuclei

• no viral protein expression except LATs, which suppress apoptosis and maintain latency

• no cytolysis → neurons survive → immune system cannot detect infected cells

• (this is immune evasion by silence and sequestration)

Step 3: reactivation

• triggered by stress, UV exposure, fever, or immunosuppression

• virus travels anterograde down the same axon to the peripheral site

• local epithelial replication → recurrent cold sore or genital lesion

• typically milder and shorter due to memory T- and B-cell response

Acquired Immune Deficiency Syndrome

The incidence of new HIV infection is increasing more slowly in many regions of the world, but AIDS is still a major disease burden

The virion of HIV

• HIV is an enveloped, positive sense, ssRNA retrovirus belonging to the Lentivirus genus

what does HIV infect

infects CD4+ T cells, macrophages, and DCs

how does HIV cause AIDs

by progressive depletion of CD4+ T cells and immune dysfunction

what is the viral envelope embedded with

viral glycoprotein spikes-gp120 and gp41, which form the env complex

what does gp120 bind to

gp120 binds to CD4 receptor and co-receptors CCR5 or CXCR4 on target cells → mediates attachment

gp120 function in life cycle

recognition of CD4, CCR5 and CXCR4 receptors

what does the HIV life cycle show

the HIV life cycle shows how the virus replicates within one cell, while the infection course shows what happens when they cycle repeats billions of times across the body, leading to immune exhaustion and AIDS if left untreated

The life cycle of HIV

Typical Course of Untreated HIV Infection

acute primary infection (2-6 weeks post exposure)

• viral load spikes dramatically (up to 10⁷ copies/microL)

• CD4+ T cells plummet due to direct infection and cytolysis in mucosal tissues

• symptoms: flu-like illness in ~50-80% of patients (fever, rash, pymphadenopathy)

• Host immune system responds: cytotoxic CD8+ T cells kill infected cells, neutralizing antibodies appear (seroconversion)

• outcome: partial control of viremia → decline in viral load → recovery of CD4 count to a lower steady state level

Clinical Latency/asymptomatic phase (~8-10 years)

Virus persists at low steady-state levels due to:

• continuous replication in lymphoid tissues

• formation of long-lived latent resevoirs in memory CD4+ T cells and macrophages

CD4+ T cells slowly decline due to chronic activation and turnover

patients remain clinically well, but immune system is gradually eroding

viral load remains stable because replication = clearance

symptomatic phase → AIDS

• When CD4+ T-cell count <200/microL, host immunity fails

• viral load surges, indicating immune exhaustion

• opportunistic infections and cancers appear

• death occurs from infection or malignancy unless treated

Targets for interfence with HIV life cycle

In principle, HIV could be attacked by therapeutic drugs at multiple points in its life cycle: virus entry, reverse transcription of viral RNA, insertion of viral cDNA in to cellular DNA by the viral integrase, cleavage of viral polyproteins by the viral protease, and assembly and budding of infectious virions

As yet, only drugs that inhibit reverse transcriptase and protease activation have been developed. Combination therpay using different kinds of drugs is more effective than using a single drug