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19.4: Immunodeficiency - Biology

19.4: Immunodeficiency - Biology



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Learning Objectives

  • Compare the causes of primary and secondary immunodeficiencies
  • Describe treatments for primary and secondary immunodeficiencies

Immunodeficiencies are inherited (primary) or acquired (secondary) disorders in which elements of host immune defenses are either absent or functionally defective. In developed countries, most immunodeficiencies are inherited, and they are usually first seen in the clinic as recurrent or overwhelming infections in infants. However, on a global scale, malnutrition is the most common cause of immunodeficiency and would be categorized as an acquired immunodeficiency. Acquired immunodeficiencies are more likely to develop later in life, and the pathogenic mechanisms of many remain obscure.

Primary Immunodeficiency

Primary immunodeficiencies, which number more than 250, are caused by inherited defects of either nonspecific innate or specific adaptive immune defenses. In general, patients born with primary immunodeficiency (PI) commonly have an increased susceptibility to infection. This susceptibility can become apparent shortly after birth or in early childhood for some individuals, whereas other patients develop symptoms later in life. Some primary immunodeficiencies are due to a defect of a single cellular or humoral component of the immune system; others may result from defects of more than one component. Examples of primary immunodeficiencies include chronic granulomatous disease, X-linked agammaglobulinemia, selective IgA deficiency, and severe combined immunodeficiency disease.

Chronic Granulomatous Disease

The causes of chronic granulomatous disease (CGD) are defects in the NADPH oxidase system of phagocytic cells, including neutrophils and macrophages, that prevent the production of superoxide radicals in phagolysosomes. The inability to produce superoxide radicals impairs the antibacterial activity of phagocytes. As a result, infections in patients with CGD persist longer, leading to a chronic local inflammation called a granuloma. Microorganisms that are the most common causes of infections in patients with CGD include Aspergillus spp., Staphylococcus aureus, Chromobacterium violaceum, Serratia marcescens, and Salmonella typhimurium.

X-Linked Agammaglobulinemia

Deficiencies in B cells due to defective differentiation lead to a lack of specific antibody production known as X-linked agammaglobulinemia. In 1952, Ogden C. Bruton (1908–2003) described the first immunodeficiency in a boy whose immune system failed to produce antibodies. This defect is inherited on the X chromosome and is characterized by the absence of immunoglobulin in the serum; it is called Bruton X-linked agammaglobulinemia (XLA). The defective gene, BTK, in XLA is now known to encode a tyrosine kinase called Bruton tyrosine kinase (Btk). In patients whose B cells are unable to produce sufficient amounts of Btk, the B-cell maturation and differentiation halts at the pre-B-cell stage of growth. B-cell maturation and differentiation beyond the pre-B-cell stage of growth is required for immunoglobulin production. Patients who lack antibody production suffer from recurrent infections almost exclusively due to extracellular pathogens that cause pyogenic infections: Haemophilus influenzae, Streptococcus pneumoniae, S. pyogenes, and S. aureus. Because cell-mediated immunity is not impaired, these patients are not particularly vulnerable to infections caused by viruses or intracellular pathogens.

Selective IgA Deficiency

The most common inherited form of immunoglobulin deficiency is selective IgA deficiency, affecting about one in 800 people. Individuals with selective IgA deficiency produce normal levels of IgG and IgM, but are not able to produce secretory IgA. IgA deficiency predisposes these individuals to lung and gastrointestinal infections for which secretory IgA is normally an important defense mechanism. Infections in the lungs and gastrointestinal tract can involve a variety of pathogens, including H. influenzae, S. pneumoniae, Moraxella catarrhalis, S. aureus, Giardia lamblia, or pathogenic strains of Escherichia coli.

Severe Combined Immunodeficiency

Patients who suffer from severe combined immunodeficiency (SCID) have B-cell and T-cell defects that impair T-cell dependent antibody responses as well as cell-mediated immune responses. Patients with SCID also cannot develop immunological memory, so vaccines provide them no protection, and live attenuated vaccines (e.g., for varicella-zoster, measles virus, rotavirus, poliovirus) can actually cause the infection they are intended to prevent. The most common form is X-linked SCID, which accounts for nearly 50% of all cases and occurs primarily in males. Patients with SCID are typically diagnosed within the first few months of life after developing severe, often life-threatening, opportunistic infection by Candida spp., Pneumocystis jirovecii, or pathogenic strains of E. coli.

Without treatment, babies with SCID do not typically survive infancy. In some cases, a bone marrow transplant may successfully correct the defects in lymphocyte development that lead to the SCID phenotype, by replacing the defective component. However, this treatment approach is not without risks, as demonstrated by the famous case of David Vetter (1971–1984), better known as “Bubble Boy” (Figure (PageIndex{1})). Vetter, a patient with SCID who lived in a protective plastic bubble to prevent exposure to opportunistic microbes, received a bone marrow transplant from his sister. Because of a latent Epstein-Barr virus infection in her bone marrow, however, he developed mononucleosis and died of Burkitt lymphoma at the age of 12 years.

Exercise (PageIndex{1})

  1. What is the fundamental cause of a primary immunodeficiency?
  2. Explain why patients with chronic granulomatous disease are especially susceptible to bacterial infections.
  3. Explain why individuals with selective IgA deficiency are susceptible to respiratory and gastrointestinal infections.

Secondary Immunodeficiency

A secondary immunodeficiency occurs as a result an acquired impairment of function of B cells, T cells, or both. Secondary immunodeficiencies can be caused by:

  • Systemic disorders such as diabetes mellitus, malnutrition, hepatitis, or HIV infection
  • Immunosuppressive treatments such as cytotoxic chemotherapy, bone marrow ablation before transplantation, or radiation therapy
  • Prolonged critical illness due to infection, surgery, or trauma in the very young, elderly, or hospitalized patients

Unlike primary immunodeficiencies, which have a genetic basis, secondary immunodeficiencies are often reversible if the underlying cause is resolved. Patients with secondary immunodeficiencies develop an increased susceptibility to an otherwise benign infection by opportunistic pathogens such as Candida spp., P. jirovecii, and Cryptosporidium.

HIV infection and the associated acquired immunodeficiency syndrome (AIDS) are the best-known secondary immunodeficiencies. AIDS is characterized by profound CD4 T-cell lymphopenia (decrease in lymphocytes). The decrease in CD4 T cells is the result of various mechanisms, including HIV-induced pyroptosis (a type of apoptosis that stimulates an inflammatory response), viral cytopathic effect, and cytotoxicity to HIV-infected cells.

The most common cause of secondary immunodeficiency worldwide is severe malnutrition, which affects both innate and adaptive immunity. More research and information are needed for the more common causes of secondary immunodeficiency; however, the number of new discoveries in AIDS research far exceeds that of any other single cause of secondary immunodeficiency. AIDS research has paid off extremely well in terms of discoveries and treatments; increased research into the most common cause of immunodeficiency, malnutrition, would likely be as beneficial.

Exercise (PageIndex{2})

  1. What is the most common cause of secondary immunodeficiencies?
  2. Explain why secondary immunodeficiencies can sometimes be reversed.

AN IMMUNOCOMPROMISED HOST

Benjamin, a 50-year-old male patient who has been receiving chemotherapy to treat his chronic myelogenous leukemia (CML), a disease characterized by massive overproduction of nonfunctional, malignant myelocytic leukocytes that crowd out other, healthy leukocytes, is seen in the emergency department. He is complaining of a productive, wet cough, dyspnea, and fatigue. On examination, his pulse is 120 beats per minute (bpm) (normal range is 60–100 bpm) and weak, and his blood pressure is 90/60 mm Hg (normal is 120/80 mm Hg). During auscultation, a distinct crackling can be heard in his lungs as he breathes, and his pulse-oximeter level (a measurement of blood-oxygen saturation) is 80% (normal is 95%–100%). He has a fever; his temperature is 38.9 °C (102 °F). Sputum cultures and blood samples are obtained and sent to the lab, but Benjamin goes into respiratory distress and dies before the results can be obtained.

Benjamin’s death was a result of a combination of his immune system being compromised by his leukemia and his chemotherapy treatment further weakening his ability to mount an immune response. CML (and leukemia in general) and corresponding chemotherapy cause a decrease in the number of leukocytes capable of normal function, leading to secondary immunodeficiency. This increases the risk for opportunistic bacterial, viral, protozoal, and fungal infections that could include Staphylococcus, enteroviruses, Pneumocystis, Giardia, or Candida. Benjamin’s symptoms were suggestive of bacterial pneumonia, but his leukemia and chemotherapy likely complicated and contributed to the severity of the pneumonia, resulting in his death. Because his leukemia was overproducing certain white blood cells, and those overproduced white blood cells were largely nonfunctional or abnormal in their function, he did not have the proper immune system blood cells to help him fight off the infection.

Table (PageIndex{1}) summarizes primary and secondary immunodeficiencies, their effects on immune function, and typical outcomes.Table (PageIndex{1}): Primary and Secondary Immunodeficiencies
DiseaseEffect on Immune FunctionOutcomes
Primary immunodeficienciesChronic granulomatous diseaseImpaired killing of bacteria within the phagolysosome of neutrophils and macrophagesChronic infections and granulomas
Selective IgA deficiencyInability to produce secretory IgAPredisposition to lung and gastrointestinal infections
Severe combined immunodeficiency disease (SCID)Deficient humoral and cell-mediated immune responsesEarly development of severe and life-threatening opportunistic infections
X-linked agammaglobulinemiaFlawed differentiation of B cells and absence of specific antibodiesRecurrent infections almost exclusively due to pathogens that cause pyogenic infections
Secondary immunodeficienciesImmunosuppressive therapies (e.g., chemotherapy, radiotherapy)Impaired humoral and/or cell-mediated immune responsesOpportunistic infections, rare cancers
MalnutritionImpaired humoral and/or cell-mediated immune responsesOpportunistic infections, rare cancers
Viral infection (e.g., HIV)Impaired cell-mediated immune responses due to CD4 T-cell lymphopeniaOpportunistic infections, rare cancers

Key Concepts and Summary

  • Primary immunodeficiencies are caused by genetic abnormalities; secondary immunodeficiencies are acquired through disease, diet, or environmental exposures
  • Primary immunodeficiencies may result from flaws in phagocyte killing of innate immunity, or impairment of T cells and B cells.
  • Primary immunodeficiencies include chronic granulomatous disease, X-linked agammaglobulinemia, selective IgA deficiency, and severe combined immunodeficiency disease.
  • Secondary immunodeficiencies result from environmentally induced defects in B cells and/or T cells.
  • Causes for secondary immunodeficiencies include malnutrition, viral infection, diabetes, prolonged infections, and chemical or radiation exposure.

Short Answer

Compare the treatments for primary and secondary immunodeficiencies.


How accurately can we assess zoonotic risk?

Identifying the animal reservoirs from which zoonotic viruses will likely emerge is central to understanding the determinants of disease emergence. Accordingly, there has been an increase in studies attempting zoonotic “risk assessment.” Herein, we demonstrate that the virological data on which these analyses are conducted are incomplete, biased, and rapidly changing with ongoing virus discovery. Together, these shortcomings suggest that attempts to assess zoonotic risk using available virological data are likely to be inaccurate and largely only identify those host taxa that have been studied most extensively. We suggest that virus surveillance at the human–animal interface may be more productive.

Citation: Wille M, Geoghegan JL, Holmes EC (2021) How accurately can we assess zoonotic risk? PLoS Biol 19(4): e3001135. https://doi.org/10.1371/journal.pbio.3001135

Academic Editor: Andy P. Dobson, Princeton University, UNITED STATES

Published: April 20, 2021

Copyright: © 2021 Wille et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: E.C.H. is funded by an Australian Research Council Australian Laureate Fellowship (FL170100022). M.W. is supported by an Australian Research Council Discovery Early Career Researcher Award (DE200100977). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist


Immunodeficiency and COVID-19 Risk

The global community has come together to try to better understand how COVID-19 may affect people who live with immunodeficiency. The risk of complications may be different depending on the type of immunodeficiency.

Primary Immunodeficiency

There are many forms of primary immunodeficiency, and they have different types and degrees of immune suppression. Broadly speaking, the information collected so far has shown that people with these conditions are not at a greater risk of experiencing severe COVID-19.

While it’s not thought that having a primary immunodeficiency is a risk factor for either contracting or having a worse course of COVID-19, it’s important to find out your individual risk. For instance, those who also live with the conditions that are known risk factors for severe COVID-19 may be at a greater risk.

There is some concern that children who are immunocompromised may be at greater risk for infection and disease. The concern is that these patients might not have the same antibody response and be able to fight off the infection as well as adults or healthy people.

However, the International Patient Organisation for Primary Immunodeficiencies acknowledges that more data is needed to understand COVID-19 in people with primary immune deficiency. To understand personal risk, patients are encouraged to speak to their doctors.

Secondary Immunodeficiency

There are many reasons people may have secondary immunodeficiency. This can include the use of certain medications, cancer (lymphomas and leukemias), treatment with radiation or chemotherapy, malnutrition, alcohol use disorder, and being older.

Those who live with certain types of secondary immune deficiencies may have an increased risk of complications. One study, for instance, showed that people with leukemia or lymphoma might have a worse outcome from COVID-19.

The Centers for Disease Control and Prevention (CDC), however, has defined which conditions put people at an increased risk of severe illness from COVID-19. Included is being in an immunocompromised state (having a weakened immune system) from having had a solid organ transplant.

COVID-19 is a new disease, data is still being collected, and other conditions not listed may also be associated with an increased risk.

The CDC has also listed the conditions for which there “might” be an increased risk for severe illness from COVID-19. These include being in an immunocompromised state (having a weakened immune system) from blood or bone marrow transplant, immune deficiencies, HIV, use of corticosteroids, or use of other immune-weakening medications.

In people who are receiving biologic medications that alter the immune system, for the most part there has not been a connection with a severe course of COVID-19. An important factor in limiting risk is keeping underlying conditions well controlled (such as avoiding flare-ups). Speak to your doctor about your individual risk.

Having a fever may be a recurring sign of certain forms of primary or secondary immunodeficiency. For that reason, some people may want to get tested for COVID-19 if they experience a fever or any other signs or symptoms. A negative test result may help in avoiding unnecessary isolation or quarantine for a suspected infection.

Patients should ask their doctors to determine if their disease or condition, or the medication they take to manage a disease, suppresses the immune system.

One small study showed that people with primary immunodeficiency and those with secondary immune deficiency who were having symptoms might fare worse with COVID-19. However, more data is needed, and the risk will depend greatly on the reason for the immune deficiency.


Clinical profile of patients with undiagnosed human immunodeficiency virus infection presenting to a local emergency department: a pilot study

Objectives: To investigate the clinical profile of patients unaware of having human immunodeficiency virus (HIV) infection on presentation to the emergency department and provide a direction for future prospective studies on undiagnosed HIV infection in emergency department patients.

Design: Retrospective, descriptive case series.

Setting: A university teaching hospital in Hong Kong. Patients Patients who were diagnosed for the first time with HIV infection or acquired immunodeficiency syndrome after presenting to the accident and emergency department from 2001 to 2011. Main outcome measures Demographic and clinical characteristics of the recruited patients.

Results: Forty-four patients satisfied the inclusion criteria and were analysed. Most patients (36%) were 40 to 49 years old. Heterosexual practice was admitted by 73% of them. Fever (48%) was the commonest presenting symptom. Ten patients died during their index admission. There were no significant differences between those who died and survivors with regard to gender, age, triage category, and CD4 cell counts. Nor were there any significant differences in gender, age distribution, and sexual orientation in these patients compared with the sample used in surveillance studies by the Centre for Health Protection in Hong Kong.

Conclusion: Patients unaware of HIV infection are not commonly encountered in accident and emergency department settings. Targeted screening of males aged between 20 and 49 years may increase the yield of HIV testing in such settings.


Extract

The human immunodeficiency virus (HIV) pandemic is unique in human history in its rapid spread, its persistence, and the depth of its impact. The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that approximately 65 million people have been infected with HIV since the beginning of the epidemic. During this time, approximately 25 million people have died from acquired immune deficiency syndrome AIDS. 1

HIV-associated morbidity and mortality was substantially reduced during the last decade following the introduction of highly active antiretroviral therapy (HAART). In spite of the striking success of HAART in treating HIV infection, many patients experience treatment failure as genetic changes emerge in the virus leading to drug resistance. 2

Laboratory testing for drug resistance in HIV strains is now used in combination with other methods to guide antiretroviral therapy. The purpose of this report is to review the background information on HIV with the focus on the problem of drug resistance and to describe the laboratory methods of testing for drug resistance in HIV strains.

Overview This section contains information on biological characteristics of HIV such as taxonomy, genetic properties, structural components, life cycle, pathogenesis, and the virulence factors.

Taxonomy Human immunodeficiency virus type 1 (HIV-1) is assigned to genus Lentivirus, subfamily Orthoretrovirinae, family Retroviridae. 3 Other human pathogens included in this family are HIV-2 (genus Lentivirus), HTLV-1, and HTLV-2 (genus Deltaretrovirus). Most cases of HIV infection worldwide are caused by HIV-1. The HIV-2 is endemic in West Africa, but cases are also reported in…

ABBREVIATIONS: ABC = abacavir AIDS = acquired immune deficiency syndrome AZT = zidovudine ddC = zalcitabine ddI = didanosine dNTP = deoxynucleotide triphosphate ddNTP = dideoxynucleotide triphosphate chain terminator d4T = stavudine FDA = Food and Drug Administration FTC = emtricitabine HIV = human immunodeficiency virus HAART = highly active antiretroviral therapy LTR = long terminal repeats NNRTI = non-nucleoside reverse transcriptase inhibitor NRTI = nucleoside analogue reverse transcriptase inhibitor PI = protease inhibitor PR = protease RT = reverse transcriptase TAM = thymidine analogue mutations TDF = tenofovir 3TC = lamivudine.

Describe the main genetic properties of the human immunodeficiency virus (HIV).

Describe the major events in the life cycle of HIV.

Identify the primary functions of each of the following viral proteins: gp120, gp41, reverse transcriptase, integrase, protease.

List the three major stages in the natural course of the HIV infection.

Describe the changes in the viral loads and the CD4 counts during the natural course of the HIV disease.

List the four FDA-approved classes of antiretroviral drugs and identify the molecular targets of therapy for each class.

Describe benefits and limitations of antiretroviral therapy.

Describe the mechanisms of resistance in each of the four FDA-approved classes of antiretroviral drugs.

List the two fundamental approaches to HIV drug resistance testing.

Describe the principles of phenotypic resistance testing and list the main steps of the testing process.

Define IC50 and calculate the X-fold reduction in susceptibility using the IC50 values.

Describe the principles of sequencing-based genotypic resistance testing and list the main steps of the testing process.

Describe the principles of dideoxynucleotide sequencing.

Describe the principles and the limitations of hybridization-based resistance assays.


Inflammation

If pathogens manage to breach the barriers protecting the body, one of the first active responses of the innate immune system kicks in. This response is inflammation . The main function of inflammation is to establish a physical barrier against the spread of infection. It also eliminates the initial cause of cell injury, clears out dead cells and tissues damaged from the original insult and the inflammatory process, and initiates tissue repair. Inflammation is often a response to infection by pathogens, but there are other possible causes, including burns, frostbite, and exposure to toxins.

The signs and symptoms of inflammation include redness, swelling, warmth, pain, and frequently some loss of function. These symptoms are caused by increased blood flow into infected tissue, and a number of other processes, illustrated in Figure 17.4.4.

Figure 17.4.4 This drawing shows what happens during the inflammatory response.

Inflammation is triggered by chemicals such as cytokines and histamines ,which are released by injured or infected cells, or by immune system cells such as macrophages (described below) that are already present in tissues. These chemicals cause capillaries to dilate and become leaky, increasing blood flow to the infected area and allowing blood to enter the tissues. Pathogen-destroying leukocytes and tissue-repairing proteins migrate into tissue spaces from the bloodstream to attack pathogens and repair their damage. Cytokines also promote chemotaxis , which is migration to the site of infection by pathogen-destroying leukocytes. Some cytokines have anti-viral effects. They may shut down protein synthesis in host cells, which viruses need in order to survive and replicate.

See the video “The inflammatory response” by Neural Academy to learn about inflammatory response in more detail:

The inflammatory response, Neural Academy, 2019.


Prognosis Prognosis

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

  • To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from MedlinePlus Genetics.

Summary

Nonionizing radiation is relatively low in energy and can be used as a heat source, whereas ionizing radiation, which is higher in energy, can penetrate biological tissues and is highly reactive. The effects of radiation on matter depend on the energy of the radiation. Nonionizing radiation is relatively low in energy, and the energy is transferred to matter in the form of heat. Ionizing radiation is relatively high in energy, and when it collides with an atom, it can completely remove an electron to form a positively charged ion that can damage biological tissues. Alpha particles do not penetrate very far into matter, whereas &gamma rays penetrate more deeply. Common units of radiation exposure, or dose, are the roentgen (R), the amount of energy absorbed by dry air, and the rad (radiation absorbed dose), the amount of radiation that produces 0.01 J of energy in 1 kg of matter. The rem (roentgen equivalent in man) measures the actual amount of tissue damage caused by a given amount of radiation. Natural sources of radiation include cosmic radiation, consisting of high-energy particles and &gamma rays emitted by the sun and other stars cosmogenic radiation, which is produced by the interaction of cosmic rays with gases in the upper atmosphere and terrestrial radiation, from radioactive elements present on primordial Earth and their decay products. The risks of ionizing radiation depend on the intensity of the radiation, the mode of exposure, and the duration of the exposure.


Watch the video: Ada Masalı. Island Tale Episode 19 English Subtitles (August 2022).