Streptococcus pneumoniae is a pathogenic gram-positive alpha hemolytic bacterium that can cause pneumonia, bacterial meningitis, otitis media and sinusitis.

The upper panel shows that strains or serotypes of S. pneumoniae have different capsular polysaccharide antigens.

The lower panel shows evidently that immunization with one serotype does not protect against another serotype.

For this reason a 23-valent pneumococcal polysaccharide vaccine (PPS23) has been developed in 1977, and used to immunize individuals over 2 years of age and older adults who are at increased risk of invasive pneumococcal disease, abbreviated as IPD.

The influenza virus expresses on its envelope surface spikes that are composed of hemagglutinin molecules, abbreviated as H, and neuraminidase molecules, abbreviated as N. Both H and N are involved in the infection process. The types of H and N vary between viral strains, and hence flu virus strains are designated as H and N with a type number, such as for example H1N1, H5N1, etc.

Let’s consider the example illustrated in the present slide: Upon infection with the influenza strain V, person P produced antibodies against various epitopes of the viral hemagglutinin. Some antibodies are neutralizing, as shown in green; others are not, as shown in blue. The left panel shows that when person P is exposed again to strain V, the neutralizing antibodies prevent the virus from infecting the patient’s cells. The center panel shows that in the course of infecting person Q, the viral strain V mutates into strain V*, which differs from V by one amino acid substitution as shown in yellow in the hemagglutinin. This amino-acid change results in the alteration of the epitope. The right panel shows that person P is not protected against Virus V* influenza virus. To clear this second influenza infection, person P must mount a primary immune response that makes neutralizing antibodies against strain V*. It is noteworthy that the viral neuraminidase also undergoes antigenic drift in a similar manner. A gradual change in antigen epitopes is referred to as antigenic drift, which can cause an epidemic.

In contrast to the previous slide on antigenic drift, a total change in epitopes is referred to as antigenic shift, which may occur by gene recombination between two different virus strains. Antigenic shift can cause a pandemic. In the present case study, the human influenza virus colored in red and the avian influenza virus colored in blue can simultaneously infect pigs, which in this context are called secondary hosts. The left panel shows a pig cell that is infected by both viruses. Viral RNA segments become re-assorted to produce a variety of recombinant viruses. The center panel shows one type of recombinant virus that has a hemagglutinin of avian origin, which is antigenically different from that of the influenza virus currently infecting the human population. The right panel shows that individual humans do not have antibodies that bind to the hemagglutinins of the avian virus, and hence their cells are infected. Because the entire human population is vulnerable to the recombinant virus, the latter has the potential to produce a pandemic influenza.

Antigenic drift can cause an epidemic of flu, whereas antigenic shift can cause a pandemic. Epidemic refers to a sudden increase in the number of cases of a disease, above the level that is normally expected in that population in that area. Pandemic refers to an epidemic that has spread over several countries or continents.

Another example of immunological escape mechanism is antigenic variation by gene conversion in the parasite African trypanosome, which is a causative agent of sleeping sickness. The top panel shows the organization of genes in the VSG locus. VSGa gene is at the expression site. The middle and bottom panels illustrate gene conversion, with VSGa being replaced by VSGb colored as a yellow box or VSGc gene shown as a blue box.

The persistence of herpes simplex, the cold sore causing agent, is another example of immunological escape. The upper panel shows that the initial infection around the lips is cleared by the immune response, and the resulting tissue damage is manifested as cold sores. In the lower panel the virus shown as small red dots has meanwhile entered some sensory neurons, for example those in the trigeminal ganglion with axons that innervate the lips, where the virus persists in a latent state. Various forms of stress can cause the virus to leave the neurons and re-infect the epithelium, thus reactivating the immune cells and causing 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.

The herpes virus varicella-zoster, which is also called herpes zoster, remains latent in one or a few ganglia after the acute infection of epithelium with chicken pox is over. Stress or immunosuppression can reactivate the virus, which then moves down the nerve and infects the skin. The reactivation of varicella zoster that causes the reappearance of the varicella rash of blisters is commonly known as shingles. Epstein Barr virus, abbreviated as EBV is another type of herpesvirus that causes a persistent infection called mononucleosis. This virus infects mononuclear cells, including B and T cells. EBV causes immunosuppression and inhibits the inflammatory response.

Some microbial toxins are designated as superantigens because of their ability to cause non-specific polyclonal activation of Th cells. The left panel shows a superantigen bound to an APC MHC-II a chain, and a CD4 T cell with TCR. The right panel shows the superantigen bound to the APC MHC-II a chain and CD4 cell TCR Vb outside of the antigen-binding site. The arrows indicate signal transduction in CD4 T cell that is mediated by CD4 binding to MHC-II, CD28 binding to B7 of the APC, and CD3 complex, which is not shown in the diagram. As you can see, superantigen does not bind to CD4 T cell antigen binding site, but to a region outside of the paratope. Since this region is common to different CD4 T cells, superantigen can trigger the activation of a large number to CD4 T cells, which together produce a massive amount of inflammatory cytokines, causing toxic shock syndrome. Toxic shock syndrome, abbreviated as TSS can be caused by superantigen produced by Streptococcus pyogenes, and as TSST for toxic shock syndrome toxin produced by Staphylococcus aureus.

Interferon gamma is an important cytokine in the host defense against infection by viral and microbial pathogens. IFN-g enhances the microbicidal function of macrophages through formation of nitric oxide and reactive oxygen intermediates. Receptors for IFN-γ are composed of a dimer of IFNγR1 and IFNγR2. The first panel shows that a dimer of IFNγR1 and IFNγR2 must be cross-linked by IFN-γ binding to the IFNγR1 chain for signaling to occur. The second panel shows that recessive mutant alleles of IFNγR1 produce a mutant chain that does not reach the cell surface. Thus, cells from patients homozygous for a recessive mutation have only IFNγR2 at the surface, and because of the lack of IFNγR1 there is no binding site for IFN-γ and consequently no response to this cytokine. Heterozygotes for such a mutation may produce sufficient numbers of wild-type chains to assemble enough functional receptors for a normal response to IFN-γ, as in the first panel. The third panel shows that 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. The fourth panel compares the results of IFN-γ stimulation of blood monocytes from normal, homozygous recessive, and heterozygous dominant patients.

Deficiency in complement system activation is associated with recurrent bacterial infections. Deficiency in factors involved in preventing the lysis of host bystander cells, such as DAF and CD59 results in autoimmune conditions. Deficiency in C1 inhibitor interferes with the down-regulation of the classical pathway, resulting in the development of hereditary angioedema.

The classical pathway of the complement system is down-regulated by C1 inhibitor, which binds to and dissociates the serine proteases C1r and C1s from C1q of the C1 complex. C1 inhibitor deficiency causes the syndrome hereditary angioedema, which is characterized by bouts of subepithelial swelling of the face, larynx, and abdomen. Swelling of the larynx can lead to suffocation.

A defect in any of the genes/proteins involved in phagocytosis is associated with recurrent bacterial and fungal infections, some of which with severe outcome. This proves the importance of phagocytosis in controlling infection.

Severe combined immunodeficiency, abbreviated as SCID is caused by the absence of T cell function. This disease is also referred to as “bubble boy” disease, who has a deficiency in IL-2R g a protein that is shared by the receptors for interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. People with SCID all immune protection from bacteria, viruses, and fungi. They are prone to repeated and persistent infections that can be very serious. Specific clinical effects associated with individual gene/protein deficiency are listed in the current table.

Adenosine deaminase or ADA deficiency is an inherited disorder that damages the immune system and causes severe combined immunodeficiency (SCID). ADA deficiency is a disorder that is caused by a mutation on the chromosome 20. Without ADA there is a build-up of toxic deoxyadenosine, which destroys T and B lymphocytes. This genetic diagram shows that both parents are healthy carriers, each having one functional copy of the ADA gene colored in red and one defective copy colored in green. Two of the eight children inherited a defective copy of the ADA gene from each parent and have ADA deficiency as labeled with a positive symbol and fully colored in red.

Some cytokine deficiency impacts negatively on the immune response. As an example, let’s consider the interaction between NK cells, macrophages and T cells in the response to infection with intracellular bacteria. The left panel shows that in the innate immune response, macrophages are activated by the IFN-γ produced by NK cells. Activated macrophages produce the cytokine IL-12, which binds to IL-12 receptors on the NK cells, and induces these cells to further secrete IFN-γ and maintain macrophage activation. The right panel shows that in the adaptive immune response, IL-12 secreted by macrophages acts on Th1 cells, and CD8 Tc cells or CTLs, and induces these cells to produce IFN-γ. In immunodeficient patients who lack the IL-12 receptor or the IFN-γ receptor, this cycle of mutual activation cannot proceed, and hence the infection persists.

HIV infection as a model of acquired immunodeficiency syndromes. In 2012 there were about 35.3 million adults and children living with HIV/AIDS worldwide, including about 2.3 million new cases of HIV infection. About 1.6 million people died from AIDS in that year.

The upper panel is an electron micrograph showing three virions, which are the infectious forms of a virus as it exists outside of the host cell. A virion consists of a nucleic acid core, a protein coat, and, in some species, an external envelope. The lower panel is a diagram of a single virion showing the envelope glycoproteins gp120 and gp41 that are encoded by the HIV RNA.

Infection with HIV starts with the binding of envelope glycoproteins to CD4 of the host Th cells. Top panel A shows the gp120 envelope protein of the virus binding to CD4 and the chemokine co-receptor CXCR4. Top panel B shows that this binding releases gp41, causing the fusion of the viral envelope with the plasma membrane and the release of the viral core into the cytoplasm. Top panel C shows that the HIV RNA genome is released and then reverse transcribed into double-stranded viral cDNA. Top panel D shows that viral cDNA migrates to the nucleus in association with the viral integrase, and then it becomes integrated into the cell genome, as a provirus.

Bottom panels A and B show that the activation of the T cell causes low-level transcription of the provirus that directs the synthesis of the early proteins Tat and Rev. Bottom panel C shows that Tat amplifies the transcription of viral RNA, while Rev increases the transport of RNA to the cytoplasm, thus expanding and changing 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. Bottom panel D shows that the new virus particles bud from the cell, acquiring their lipid envelope and envelope glycoproteins in the process.

This diagram illustrates the gradual declined in the number of CD4 T cells in peripheral blood as shown by the green line. Opportunistic infections and other symptoms become more frequent as the CD4 T-cell count falls, starting at around 500 cells/μl. The disease then enters the symptomatic phase. When CD4 T-cell counts fall below 200 cells per μl, the patient is said to have AIDS.

Shown in this table are the most common opportunistic infections that kill AIDS patients in developed countries. The malignancies are listed separately but they are also the result of impaired responses to infectious agents.