Ch 13 Failure of the Body's Defenses

What are 7 protein deficiencies in the pathways of complement activation that cause disease?

1. C1, C2, C4 • immune complex disease • early C components are for immune complex clearance • defective classical pathway 2. C3 • susceptibility to encapsulated bacteria • affects all complement activation pathways 3. C5-C9 • susceptibility to Neisseria • no formation of PMC 4. factor D, properdin (factor P) • susceptibility to encapsulated bacteria and Neisseria • but no immune-complex disease 5. factor I • similar effects to C3 deficiency 6. DAF, CD59 • autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria 7. C1INH • hereditary angiodema (HAE)

What are 5 examples of bacteria with other strategies?

1. Mycobacterium tuberculosis • prevents phagolysosome formation • survives inside the vesicle 2. Listeria monocytogenes • grows and multiplies in cytoplasm of macrophages 3. T. gondii • surrounds itself with a membrane 4. T. pallidum • coats itself with human protein 5. Staph coagulase • capsulated bacteria are virulent

What are 9 severe immunodeficiencies caused by the absence of T-cell function?

1. adenosine deaminase deficiency 2. radiation-sensitive SCID 3. X-linked SCID 4. janus-3-kinase (Jak3) deficiency 5. omenn syndrome 6. complete DiGeorge syndrome 7. Wiskott-Aldrich syndrome (WAS) 8. MHC-I deficiency 9. MHC-II deficiency • T-cells function in all aspects of adaptive immunity - (unlike B cells which are involved in humoral immunity) • mutation in any gene coding for cytokines can lead to immunodeficiency - i.e. SCID: Rag proteins

What are 23 inherited immunodeficiency syndromes that reveal the mechanisms of human immunity?

1. asplenia 2. C3 deficiency 3. factor I deficiency 4. deficiencies of C5, C6, C7, C8 or C9 5. paroxysmal nocturnal hemoglobinuria 6. NEMO deficiency / X-linked hypohidrotic ectodermal dysplasia and immunodeficiency 7. chronic granulomatous disease 8. MBL deficiency 9. NK-cell deficiency 10. hyper-IgM deficiency 11. IgG2 deficiency 12. SCID 13. Omenn syndrome 14. MHC class I deficiency / bare lymphocyte syndrome type I 15. pre-B-cell receptor deficiency 16. X-linked agammaglobulinemia 17. complete DiGeorge syndrome 18. APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) 19. IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) 20. ZAP-70 deficiency 21. C4A or C4B 23. selective IgA deficiency

What are 6 ways for microbes to be established as pathogens that are "smarter" than the immune system?

1. genetic variations 2. mutations 3. gene rearrangements 4. latency 5. subvert immune mechanisms 6 superantigens

What are 3 examples of herpesviruses?

1. herpes simplex virus 2. varicella zoster virus 3. EBV • persist in human hosts by hiding from the immune response - escape by going into latency (no sign of infection)

What are 2 specific mechanisms by which herpesviruses and poxviruses block antigen processing and presentation?

1. inhibition of MHC class I upregulation by IFN-γ 2. inhibition of peptide transport by TAP

What are the 4 viral strategies by which herpesviruses and poxviruses subvert the immune response?

1. inhibition of humoral immunity 2. inhibition of inflammatoy response 3. blocking of antigen processing and presentation 4. immunosuppression of host • herpes simplex, cytomegalovirus, and Epstein-Barr viruses are herpesviruses • vaccinia is a poxvirus

What are 4 syndomes characterized by persistent bacterial infections due to genetic defects that affect phagocytes?

1. leukocyte adhesion deficiency (LAD) 2. chronic granulomatous disease (CGD) 3. glucose-6-phosphate dehydrogenase (G6PD) deficiency 4. myeloperoxidase deficiency (MPOD) 5. Chediak-Higashi syndrome

What are the 4 types of microbes?

1. protozoans 2. fungi 3. bacteria 4. virus • immunity counters their onslaught • not all microbes are pathogenic - don't have mechs or produce proteins that can overcome immune system

What are 3 specific mechanisms by which herpesviruses and poxviruses inhibit humoral immunity?

1. virally encoded Fc receptor 2. virally encoded COMPLEMENT receptor 3. virally encoded complement CONTROL protein

What are 4 specific mechanisms by which herpesviruses and poxviruses inhibit the inflammatory response?

1. virally encoded chemokine receptor homolog 2. virally encoded soluble cytokine receptor 3. viral inhibition of adhesion molecule expression 4. protection from NFκB activation by short sequences that mimic TLRs

MHC class I deficiency

A defect in either of the two genes encoding the TAP peptide transporter (see Section 5-11) impedes the binding of peptides by HLA class I molecules, lead- ing to an unusually low abundance of HLA class I molecules on cell surfaces. This form of immunodeficiency, called MHC class I deficiency, is less severe than the immunodeficiency caused by the absence of HLA class II, its princi- pal effect being the selective loss of CD8 T cells (see Section 7-10) and of cyto- toxic T-cell responses to intracellular infections.

Chédiak-Higashi syndrome

A different phenotype char- acterizes Chédiak-Higashi syndrome, in which phagocytosed materials are not delivered to lysosomes because of a defect in the vesicle fusion mecha- nism. This lack of phagocyte function has effects in many different organs as well as leading to persistent and recurrent bacterial infections. The mutations causing this disease are in the CHS1 gene on chromosome 1, which encodes the lysosomal trafficking protein that is critical for lysosome function.

X-linked SCID

Because of the unique inheritance pattern of the X chromosome, X-linked dis- eases are more easily discovered, and at least two forms of SCID are of this type. The one we consider here is due to mutation in the X-linked gene that encodes the common gamma chain (γc), a shared signaling component of the cell-surface receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. (This γ chain of cytokine receptors is not the same as the γ chain associated with Fc receptors). When one of these cytokines binds to its receptor, γc interacts with the protein kinase Jak3 to produce intracellular signals. In the absence of a functional γ chain, none of the five cytokines can induce receptor signaling and so, predictably, the result is SCID. A very similar, but autosom- ally inherited, immunodeficiency occurs in patients who lack Jak3. The pheno- type of SCID is so severe that affected infants survive only if their immune system is replaced by hematopoietic cell transplantation.

Describe the inheritance of adenosine deaminase (ADA) deficiency in a family.

Both parents are healthy carriers having 1 functional (red) and 1 defective (green) copy of the ADA gene. • autosomally inherited Two of the eight children inherited a defective copy of the ADA gene from each parent and have ADA deficiency (+). * males are indicated by squares * females are indicated by circles

adenosine deaminase deficiency

Deficiency of ADA or PNP account for 15% of SCID patients. • ADA = adenosine deaminase • PNP = purine nucleoside phosphorylase • enzymes involved in PURINE DEGRADATION The absence of these enzymes causes an accumulation of NUCLEOTIDE METABOLITES in all types of human cell. The effects are particularly TOXIC to developing T cells and, to much lesser extent, to developing B cells. Infants with these immunodeficiencies have an UNDERDEVELOPED THYMUS that contains few lymphocytes.

CD40 ligand deficiency

Diminished production of antibodies is a symptom of defective genes encoding the membrane-associated cytokine CD40 ligand. Interaction of CD40 ligand on activated T cells with B-cell CD40 is a crucial part of the T-cell help given to B cells. • macrophage also uses CD40R reacting with CD40L on T cells - 🡪 neutropenia This stimulates B-cell activation, the development of germinal centers, and isotype switching. CD40 ligand is encoded on the X chromosome, so most patients with a hereditary deficiency in CD40 ligand are males. In the absence of CD40 ligand, virtually no specific antibody is made against T-cell dependent antigens and there are no germinal centers in the secondary lymphoid tissues. The blood of these patients has extremely low amounts of IgG, IgA, and IgE combined with abnormally high amounts of IgM. • no isotype switching This latter characteristic led to the condition being named X-linked hyper-IgM syndrome. Patients with this immunodeficiency are inherently susceptible to infection with pyogenic bacteria. As for XLA patients, regular infusions of intravenous immunoglobulin help to prevent infections, and antibiotics are used to treat their infections.

Describe the mutual activation of macrophages and effector lymphocytes in the immune response to intracellular bacterial infections.

In the INNATE immune response... • macrophages are activated by the IFN-γ made by NK cells and in turn produce the cytokine IL-12 • this binds to IL-12 receptors on the NK CELLS, inducing further secretion of IFN-γ and maintenance of macrophage activation In the ADAPTIVE immune response... • IL-12 secreted by macrophages acts on TH1 CELLS, inducing their differentiation into IFN-γ-secreting TH1 cells • CD8 CYTOTOXIC T cells (CTLs) also respond to the IL-12 made by the macrophage and they too produce IFN-γ In immunodeficient patients lacking the... • IL-12 receptor • IFN-γ recepto ...this cycle of mutual activation cannot proceed, so infection persists → mycobacterial infections

Describe how persistence and reactivation of herpes simplex virus infection.

Initial infection around the lips is cleared by the IMMUNE RESPONSE, and the resulting tissue damage is manifested as cold sores. The virus has meanwhile entered SENSORY NEURONS, where the virus persists in a latent state. • i.e. trigeminal ganglion with axons that innervate the lips Various forms of stress can cause the virus to LEAVE the neurons and reinfect the epithelium. This REACTIVATES the immune response and causes cold sores. People infected with herpes simplex viruses get cold sores periodically as a result of this process. During its active phase, the virus can pass from one person to another.

MHC class II deficiency

Lack of HLA class II molecules also causes a serious immunodeficiency. The deficiency was originally named 'bare lymphocyte syndrome' because the defect was first discovered on B lymphocytes, the major population of periph- eral blood cells that expresses HLA class II, but is now more often called MHC class II deficiency. In these patients, CD4 T cells fail to develop (see Section 7-10), which compromises most aspects of adaptive immunity. MHC class II deficiency arises from defects in transcriptional regulators that are essential for the expression of all the HLA class II genes. A homozygous defect in any one of four proteins produces the condition. One protein is the class II trans- activator (CIITA), the other three are components of RFX, a transcriptional complex that binds to a conserved sequence in the promoter of HLA class II genes called the X box.

leukocyte adhesion deficiency

Phagocytosis mediated by macrophages and neutrophils is the principal method by which the immune system gets rid of infecting bacteria and other microbes. Any deficiency that compromises phagocyte activity has profound effects on the immune system's capacity to clear infection (Figure 13.15). One such syndrome is due to mutation of the CD18 gene and is known as leuko- cyte adhesion deficiency. CD18 is the β2 subunit of the leukocyte integrins, which comprise the CR3, CR4, and LFA-1 adhesion molecules that are neces- sary for neutrophils and monocytes to leave the blood and enter sites of infec- tion (see Section 3-8). In children with leukocyte adhesion deficiency, these cells are unable to enter infected tissues where they are needed to dispose of the infecting pathogen. Because CR3 and CR4 also function as complement receptors, a second defect is that the phagocytes are unable to engulf bacteria opsonized with complement (see Section 3-9). Children with leukocyte adhe- sion deficiency have recurrent and persistent infections with pyogenic bacte- ria. These respond poorly to antibiotics and are not cleared by seemingly normal B-cell and T-cell responses. Children with leukocyte adhesion defi- ciency suffer successive infections and usually succumb during the first 2 years of life.

IFN-γ receptor deficiency

The response of macrophages to IFN-γ is crucial for defense against intravesicular bacteria, such as mycobacteria, and both dominant and recessive mutations in IFNγR1 have been identified in patients suffering from persistent mycobacterial infections. Both types of mutation cause the condition of IFN-γ receptor deficiency. The recessive alleles contain mutations that prevent any expression of IFNγR1 at the cell surface. The macrophages and monocytes of patients with 2 recessive alleles carry only IFNγR2 at their surfaces and are unresponsive to IFN-γ. For this group of patients the disease is usually more severe and appears at an earlier age. Heterozygotes are healthy because the protein made from the defective allele does not interfere with that made from the normal allele, which assembles with IFNγR2 and moves to the cell surface as functional IFN-γ receptor.

Describe how bacterial superantigens activate CD4 T cells by cross-linking MHC class II molecules with α:β T-cell receptors and CD28 co-stimulatory molecules in the absence of antigenic peptides.

The superantigen first BINDS MHC class II. It then engages the Vβ chain and CD28. Signals from the TCR, CD4 co-receptor, and CD28 combine to ACTIVATE the T cell. • cytokines IL1, IL2, and TNFα → systemic shock • antigen-specific T cells undergo apoptosis In the molecular model, staphylococcal enterotoxin (blue) interacts with an • MHC class II molecule - (yellow and green) • α:β TCR - (orange, gray, and pink) A peptide bound by the MHC class II molecule (red) is NOT recognized by the TCR.

Describe the virion of human immunodeficiency virus (HIV)

The upper panel is an electron micrograph showing 3 virions. The lower panel is a diagram of a single virion. gp120 and gp41 are virally encoded envelope glycoproteins of molecular masses 120 kDa and 41 kDa that form the viral spike. • RNA → DNA→ provirus - integrates in host genome • causes slow disease (Lentivirus)

herpes simplex virus

cause of cold sores • epithelial cells - cold sore - killed by immune response • neurons - latency - not killed by immune response - don't express many MHC-1, so hard for CD8 cytotoxic cells to do their job (escape detection) • reactivation - sore again - mediated by cytotoxic T cells

Epstein-Barr virus (EBV)

cause of infectious mononucleosis • B cells are primary targets • EBNA-1 is a viral protein that is not degraded by proteosome and therefore not attached to MHC-1

hereditary angioedema

characterized by bouts of subepithelial swelling of the face, larynx, and abdo- men. The swelling around the larynx can lead to death by suffocation. C1 inhibitor affects serine proteases such as C1r and C1s by binding to the active site and forming a covalent bond that irreversibly inactivates the enzyme. In patients deficient in C1 inhibitor the classical pathway is overactive, causing abnormally low levels of C2 and C4 in the blood and unusually high produc- tion of the vasoactive C2a fragment.

secondary immunodeficiency diseases

immunodeficiency due to ENVIRONMENTAL factors • i.e. immunosupressive drugs - managed better since advent of antibiotic therapy

primary immunodeficiency diseases

inherited immunodeficiency disease due to DEFECTIVE GENE • susceptibility to infection • autoimmunity One way to study immunology is to knockout selected genes and study the phenotype (in mouse). • can not be done in humans • but there are about 150 natural KO in the form of primary ID disease Most of these diseases are rare and seen in isolated populations. • advanced genomics and genetics have helped identify the gene They are caused by dominant, recessive, or X-linked defects. • dominant - defective allele is dominant (over normal allele) • recessive - manifestation only when both alleles are defective - carriers: only 1 allele is defective • X-linked - occurs in male (as they have only one X gene) - in female: only if both their alleles are defective

What is the specific mechanisms by which herpesviruses and poxviruses immunosuppress the host?

virally encoded cytokine homolog of IL-10

acquired immunodeficiency syndrome (AIDS)

• HIV = human immuno virus - retrovirus - has enzyme reverse transcriptase - 2 types: HIV-1 and HIV-2 - CD4 cells targeted • AIDS is one of the newest diseases

Describe how immune response can contribute to disease.

• immune response overreacts to pathogen instead of clearing them from the body • respiratory syncytial virus (RSV) and overproduction of TH2 cells (instead of cytotoxic T cells) • after immunization, natural (secondary) infection caused over production of IL-3,4,5 - induced bronchospasm - increased mucus secretion - recruitment of eosinophils • 90,000 admissions and 4,500 deaths each year in US

varicella zoster virus

• infects dorsal root ganglia • primary infection: chicken pox • secondary infection: shingles

acute infectious mononucleosis

Epstein-Barr virus (EBV) is a herpesvirus to which most humans are exposed that causes persistent infection. First exposure in childhood produces a mild cold-like disease, whereas adolescents or adults encountering EBV for the first time develop infectious mononucleosis (also known as glandular fever), an acute infection of B lymphocytes. EBV infects B cells by binding to the CR2 component of the B-cell co-receptor complex. Most of the infected B cells proliferate and produce virus, leading in turn to the stimulation and proliferation of EBV-specific T cells. The result is an unusually large number of mononuclear white blood cells (lymphocytes, mostly T cells), which gives the disease its name. After some time, the acute infection is brought under control by CD8 cytotoxic T cells, which kill the virus-infected B cells. The virus persists in the body, however, because a minority of B cells become latently infected. This involves shutting off the synthesis of most viral proteins except EBNA-1, which maintains the viral genome in these cells. Latently infected cells do not present a target for attack by CD8 cytotoxic cells because the proteasome is unable to degrade EBNA-1 into peptides that are bound and presented by MHC class I molecules.

Describe the genes and proteins of HIV-1.

HIV-1 has an RNA genome consisting of 9 genes flanked by long terminal repeats (LTRs). The products of the 9 genes and their known functions are tabulated. Several of the viral genes are overlapping and are read in different frames. Others encode large polyproteins that after translation are cleaved to produce several proteins having different activities. The gag, pol, and env genes are common to all retroviruses, and their protein products are all present in the virion.

Describe the evolution of new influenza virus variants by antigenic shift.

Human (red) and avian (blue) influenza viruses can simultaneously infect pigs, which in this context are called SECONDARY HOSTS. In a pig cell that is infected by both viruses, their RNA segments become reassorted to produce a variety of RECOMBINANT VIRUSES. One type of recombinant virus has a hemagglutinin of avian origin. The avian hemagglutinin is antigenically very DIFFERENT from the hemagglutinins of the influenza viruses currently infecting the human population, including the one that infected the pig cell. Individual humans are highly susceptible to the recombinant virus because they do NOT have antibodies that bind to the hemagglutinin and prevent the virus from infecting cells. Because the entire human population is VULNERABLE to the recombinant virus, the latter has the potential to produce a pandemic influenza. • i.e. H5N1 - common in animals - only a few mutations away from becoming pandemic flu

Describe how B cells do not develop beyond the pre-B cell stage in patients with X-linked agammaglobulinemia (XLA).

In XLA, Bruton's tyrosine kinase is defective. • contributes to intracellular signaling from the BCR • necessary for the development and differentiation of pre-B cells In patients with this disease, B cells become arrested at the pre-B-cell stage because intracellular signals cannot be generated by the pre-B-cell receptor. Most patients with XLA are males because males have only one copy of the X chromosome. Heterozygous females are carriers of the disease trait although healthy themselves. During development, female cells randomly inactivate one of their X chromosomes. Consequently, half of the developing B cells in a female carrier become arrested at the pre-B-cell stage because they have inactivated the X chromosome that carries the good copy of the BTK gene. The other half develop to become functional B cells because they have inactivated the X chromosome that carries the bad copy of BTK and thus use the X chromosome having the good copy. * Although BTK is also expressed in monocytes and T cells, these cells are not obviously compromised by its absence in patients with XLA.

chronic granulomatous disease

In chronic granulomatous disease (CGD), the antibac- terial activity of phagocytes is compromised by their inability to produce the superoxide radical O2 - (see Section 3-9). Mutations affecting any of the four proteins of the NADPH oxidase system can produce the phenotype. Patients with this disease suffer from chronic bacterial infections, often leading to granuloma formation. Deficiencies in the enzymes glucose-6-phosphate dehydrogenase and myeloperoxidase also impair intracellular bacterial kill- ing, leading to a similar but less severe phenotype.

Describe the impact of recessive and dominant mutations in the IFN-γ receptor on monocyte activation.

Receptors for IFN-γ are composed of a dimer of IFNγR1 and IFNγR2. Two such dimers must be cross-linked by IFN-γ binding to the IFNγR1 chain for signaling to be triggered. RECESSIVE mutant alleles of IFNγR1 produce a mutant chain that does not reach the surface. Thus, cells from patients homozygous for a recessive mutation: • have only IFNγR2 at the surface • lack IFNγR1 function • cannot respond to IFN-γ Heterozygotes for such a mutation produce sufficient numbers of wild-type chains to assemble enough FUNCTIONAL receptors for a normal response to IFN-γ. DOMINANT mutant alleles of IFNγR1 produce a mutant chain lacking a signaling domain. This chain can assemble into a dimer and bind IFN-γ, but cannot signal. Heterozygotes for a dominant mutation make a small number of functional receptors composed entirely of wild-type chains, but most receptors are NONFUNCTIONAL. Thus their response to IFN-γ is defective. • severe immunodeficiency results The graph compares the results of IFN-γ stimulation of blood monocytes from normal, homozygous recessive, and heterozygous dominant patients. • monocyte/macrophage are activated by IFNγ • helper-T-cells and cytotoxic T cells produce IFNγ

Describe how protective immunity against Streptococcus pneumoniae is serotype-specific.

Strains, or serotypes, of S. pneumoniae have antigenically different capsular polysaccharides. Antibodies against capsular polysaccharides opsonize the pathogen and enable it to be phagocytosed. A person infected with one serotype of S. pneumoniae clears the infection with type-specific antibody. These antibodies, however, have no protective effect when the same person is infected with a different serotype of S. pneumoniae. The second infection can be cleared only by making a new primary immune response that is directed specifically at the second serotype.

Describe the evasion of IgA- mediated defense by staphylococcal superantigen-like protein 7.

The combination of specific IgA and FcαRI on phagocytes causes the elimination of bacteria that cross a mucosal barrier and infect the underlying tissue. This mechanism for disposing of bacteria is thwarted by the SSLP7 protein of S. aureus. • SSLP7 = staphylococcal superantigen-like protein 7 By binding to both C5 and the Fc region of IgA, SSLP7 prevents IgA from binding to FcαRI or activating complement-mediated killing of the bacteria (not shown). • host produces IgA for newest SSLP • bacteria produces new SSLP that do not bind IgA

Describe the life cycle of HIV in human cells.

The gp120 envelope protein of the virus binds to CD4, enabling gp120 to also bind the chemokine CO-RECEPTOR. This binding releases gp41, causing fusion of the viral envelope with the plasma membrane and release of the viral core into the cytoplasm. The RNA genome is released and reverse transcribed into double-stranded cDNA. This DNA migrates to the nucleus in association with the viral integrase, and becomes integrated into the cell genome, as a provirus (top panels). Activation of the T cell causes low-level transcription of the provirus that directs the synthesis of the early proteins Tat and Rev. These then expand and change the pattern of provirus transcription to produce mRNA encoding the protein constituents of the virion and RNA molecules corresponding to the HIV genome. Envelope proteins travel to the plasma membrane, whereas other viral proteins and viral genomic RNA assemble into nucleocapsids. New virus particles bud from the cell, acquiring their lipid envelope and envelope glycoproteins in the process.

Describe how antigenic variation by African trypanosomes allows them to escape from adaptive immunity.

Trypanosomes are protozoan parasites that possesses over 1000 genes coding for variable surface glycoproteins (VSGs) • N. gonorrhoea - pilin gene similar to that of trypanosoma (have family of variant genes) • S. typhimurium - alternate expression of flagelin Trypanosomes use gene rearrangement on VSG locus to change their surface antigens. 1. VSGa gene (red box) is in the expression site, and the VSGb (yellow box) and VSGc gene (blue box) are inactive 2. gene conversion has replaced VSGa with VSGb at the expression site 3. VSGc has replaced VSGb at the expression site. The patient's parasite burden (red, yellow, blue, and green lines) and antibody response (dotted black lines) co-evolve throughout the infection. • host makes antibody response to the dominant form of VSG • minority forms then dominate In the 1st week... • TRYPANOSOMES expressing VSGa proliferate (red line) • but their numbers decline as anti-VSGa antibody is produced In the 2nd week... • SELECTION PRESSURE imposed by anti-VSGa antibody enables PARASITES expressing VSGb to proliferate (yellow line) • decline when anti-VSGb antibody is made In the 3rd week... • PARASITES expressing the VSGc gene dominate In the 4th week... • it is the turn of parasites expressing VSGd to dominate • and so on, until the patient dies from all the DAMAGE caused by the succession of primary immune responses

Describe the evolution of new influenza variants by antigenic drift.

Upon infection with influenza strain V, person P produced antibodies against various epitopes of the viral hemagglutinin. • some antibodies are neutralizing (green) • others are not (blue) When person P is further exposed to STRAIN V, the neutralizing antibodies prevent the virus from infecting cells. In the course of infecting person Q, viral strain V mutates to give strain V*. • strain V* differs from V by 1 amino acid substitution (yellow) in the hemagglutinin This amino-acid difference eliminates the epitope recognized by neutralizing antibodies made against strain V. Consequently, STRAIN V* influenza virus can infect cells of person P without interference from the antibodies made against strain V. To clear this second influenza infection, person P must mount a primary immune response that makes neutralizing antibodies against strain V*. The viral neuraminidase (not shown) undergoes antigenic drift in a similar manner. • resistant strains survive to infect new host the next season

Wiskott-Aldrich syndrome

WAS is... • another X-linked deficiency of T-cell function • syndrome involving the impairment of platelets as well as lymphocytes It shows up in childhood as a history of recurrent infections, but is less immunologically severe than SCID. The patients have normal levels of T and B cells, but they cannot make good antibody responses and are therefore kept on a course of intravenous immunoglobulin. The relevant gene on the X chromosome encodes the Wiskott-Aldrich syndrome protein (WASP). This protein is involved in the... • cytoskeletal REORGANIZATION that is needed before T cells can deliver cytokines • SIGNALS to the B cells, macrophages and other target cells with which they form cognate interactions ...during their development and participation in the immune response

X-linked severe combined immunodeficiency

Whereas B cells contribute only to the antibody response, T cells function in all aspects of adaptive immunity. This means that inherited defects in the mech- anisms of T-cell development and T-cell function have a general depressive effect on the immune system's capacity to respond to infection. Patients with T-cell deficiencies tend to be susceptible to persistent or recurrent infections with a broader range of pathogens than patients with B-cell deficiencies (Figure 13.16). Those patients who make neither T-cell-dependent antibody responses nor cell-mediated immune responses are said to have severe com- bined immune deficiency (SCID).